Reviewed, UniProtKB/Swiss-Prot P49768 (PSN1_HUMAN)

Names and origin

Protein names

Recommended name:
    Presenilin-1
      Short name=PS-1
    EC=3.4.23.-
Alternative name(s):
    Protein S182
Cleaved into the following 3 chains:
    1- Recommended name:
            Presenilin-1 NTF subunit
    2- Recommended name:
            Presenilin-1 CTF subunit
    3- Recommended name:
            Presenilin-1 CTF12
                Short name=PS1-CTF12

Gene names

Name:	PSEN1
Synonyms:	AD3, PS1, PSNL1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	467 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis. Ref.17 Ref.19 Ref.22 Ref.23 Ref.24 Ref.25 Ref.34 Ref.37
Subunit structure	Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity. Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Associates with NOTCH1. Component of cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2, CTNNB1, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with isoform 3 of GFAP. Interacts with DOCK3 By similarity.
Subcellular location	Endoplasmic reticulum membrane; Multi-pass membrane protein. Golgi apparatus membrane; Multi-pass membrane protein. Cell surface. Note: Bound to NOTCH1 also at the cell surface. Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane. Also present in azurophil granules of neutrophils. Ref.11 Ref.15 Ref.26 Ref.29
Tissue specificity	Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes. Ref.11 Ref.26
Domain	The PAL motif is required for normal active site conformation.
Post-translational modification	Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12. Ref.12 Ref.14 After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis. Ref.13 Ref.33 Ref.36 Ref.40
Involvement in disease	Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. Ref.1 Ref.28 Ref.41 Ref.42 Ref.43 Ref.44 Ref.45 Ref.46 Ref.47 Ref.48 Ref.49 Ref.52 Ref.53 Ref.54 Ref.55 Ref.56 Ref.57 Ref.59 Ref.60 Ref.61 Ref.62 Ref.63 Ref.64 Ref.65 Ref.66 Ref.67 Ref.68 Ref.70 Ref.71 Ref.72 Ref.73 Ref.74 Ref.75 Defects in PSEN1 are a cause of frontotemporal dementia [MIM:600274]. Ref.69
Sequence similarities	Belongs to the peptidase A22A family.

Ontologies

Keywords
Biological process	Apoptosis Cell adhesion Notch signaling pathway
Cellular component	Endoplasmic reticulum Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Alzheimer disease Amyloidosis Disease mutation Neurodegeneration
Domain	Transmembrane
Molecular function	Hydrolase Protease
PTM	Phosphoprotein
Technical term	Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	Notch receptor processing Ref.10 Traceable author statement. Source: HGNC amyloid precursor protein catabolic process Ref.10 Traceable author statement. Source: HGNC anti-apoptosis Traceable author statement. Source: ProtInc apoptosis Inferred from Experiment. Source: Reactome cell-cell adhesion Inferred from mutant phenotype. Source: MGI chromosome segregation Ref.22 Traceable author statement. Source: ProtInc endoplasmic reticulum calcium ion homeostasis Inferred from direct assay. Source: MGI induction of apoptosis by extracellular signals Inferred from Experiment. Source: Reactome intracellular signaling cascade Inferred from electronic annotation. Source: InterPro membrane protein ectodomain proteolysis Ref.10 Inferred from direct assay. Source: HGNC membrane protein intracellular domain proteolysis Inferred from Experiment. Source: Reactome positive regulation of catalytic activity Ref.10 Inferred from direct assay. Source: HGNC regulation of phosphorylation Inferred from direct assay. Source: UniProtKB
Cellular component	Golgi apparatus Ref.10 Inferred from direct assay. Source: MGI cell surface Inferred from electronic annotation. Source: UniProtKB-SubCell endoplasmic reticulum Ref.10 Inferred from direct assay. Source: MGI integral to nuclear inner membrane Traceable author statement. Source: ProtInc integral to plasma membrane Ref.10 Inferred from direct assay. Source: HGNC kinetochore Traceable author statement. Source: ProtInc membrane fraction Traceable author statement. Source: ProtInc mitochondrion Inferred from direct assay. Source: UniProtKB nuclear outer membrane Inferred from direct assay. Source: MGI
Molecular function	PDZ domain binding Ref.18 Inferred from physical interaction. Source: UniProtKB beta-catenin binding Inferred from physical interaction. Source: MGI endopeptidase activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APP	P05067	1	EBI-297277,EBI-77613
APP	P05067-4	1	EBI-297277,EBI-302641
APP	P05067-8	1	EBI-297277,EBI-302661
CTNNB1	P35222	2	EBI-297277,EBI-491549
Ctnnb1	Q02248	1	EBI-297277,EBI-397872	From a different organism.
JUP	P14923	3	EBI-297277,EBI-702484
MTCH1	Q9NZJ7	1	EBI-297277,EBI-297455
TMED10	P49755	2	EBI-297277,EBI-998422

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P49768-1)

Also known as: I-467;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P49768-2)

Also known as: I-463;

The sequence of this isoform differs from the canonical sequence as follows:
     26-29: Missing.

Isoform 3 (identifier: P49768-3)

Also known as: I-374;

The sequence of this isoform differs from the canonical sequence as follows:
     26-29: Missing.
     319-467: STERESQDTV...DQLAFHQFYI → RACLPPAAIN...RNGKPRGTVI

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 4 (identifier: P49768-4)

Also known as: Minilin;

The sequence of this isoform differs from the canonical sequence as follows:
     162-184: IHAWLIISSLLLLFFFSFIYLGE → SMRHRSLLSTLFFLWLGILVTVT
     185-467: Missing.

Isoform 5 (identifier: P49768-5)

The sequence of this isoform differs from the canonical sequence as follows:
     319-467: STERESQDTV...DQLAFHQFYI → RACLPPAAIN...RNGKPRGTVI

Isoform 6 (identifier: P49768-6)

The sequence of this isoform differs from the canonical sequence as follows:
     319-376: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 298	298	Presenilin-1 NTF subunit		PRO_0000025591
	Chain	299 – 467	169	Presenilin-1 CTF subunit		PRO_0000025592
	Chain	346 – 467	122	Presenilin-1 CTF12		PRO_0000236055
Regions
	Topological domain	1 – 82	82	Cytoplasmic Potential
	Transmembrane	83 – 103	21	Potential
	Topological domain	104 – 132	29	Lumenal Potential
	Transmembrane	133 – 153	21	Potential
	Topological domain	154 – 160	7	Cytoplasmic Potential
	Transmembrane	161 – 181	21	Potential
	Topological domain	182 – 190	9	Lumenal Potential
	Transmembrane	191 – 211	21	Potential
	Topological domain	212 – 220	9	Cytoplasmic Potential
	Transmembrane	221 – 241	21	Potential
	Topological domain	242 – 243	2	Lumenal Potential
	Transmembrane	244 – 264	21	Potential
	Topological domain	265 – 407	143	Cytoplasmic Potential
	Transmembrane	408 – 428	21	Potential
	Transmembrane	433 – 453	21	Potential
	Topological domain	454 – 467	14	Cytoplasmic Potential
	Region	322 – 450	129	Required for interaction with CTNNB1
	Region	372 – 399	28	Required for interaction with CTNND2
	Region	464 – 467	4	Interaction with MTCH1
	Motif	433 – 435	3	PAL
	Compositional bias	94 – 97	4	Poly-Val
	Compositional bias	171 – 174	4	Poly-Leu
	Compositional bias	418 – 425	8	Poly-Leu
Sites
	Active site	257	1	Probable
	Active site	385	1	Probable
	Site	291 – 292	2	Cleavage; alternate
	Site	292 – 293	2	Cleavage; alternate
	Site	298 – 299	2	Cleavage
	Site	345 – 346	2	Cleavage; by caspase
Amino acid modifications
	Modified residue	43	1	Phosphoserine Ref.36 Ref.40
	Modified residue	310	1	Phosphoserine; by PKA Ref.33
	Modified residue	346	1	Phosphoserine; by PKC Ref.33
	Modified residue	365	1	Phosphoserine Ref.40
	Modified residue	367	1	Phosphoserine Ref.40
Natural variations
	Alternative sequence	26 – 29	4	Missing in isoform 2 and isoform 3.		VSP_005191
	Alternative sequence	162 – 184	23	IHAWL…IYLGE → SMRHRSLLSTLFFLWLGILV TVT in isoform 4.		VSP_007986
	Alternative sequence	185 – 467	283	Missing in isoform 4.		VSP_007987
	Alternative sequence	319 – 467	149	STERE…HQFYI → RACLPPAAINLLSIAPMAPR LFMPKGACRPTAQKGSHKTL LQRMMMAGSVRNGKPRGTVI in isoform 3 and isoform 5.		VSP_005192
	Alternative sequence	319 – 376	58	Missing in isoform 6.		VSP_012288
	Natural variant	79	1	A → V in AD3; no effect on interaction with GFAP. Ref.28 Ref.52 Ref.66		VAR_006413
	Natural variant	82	1	V → L in AD3; no effect on interaction with GFAP. Ref.28 Ref.42 Ref.59		VAR_006414
	Natural variant	92	1	C → S in AD3. Ref.68		VAR_016214
	Natural variant	96	1	V → F in AD3. Ref.45		VAR_006415
	Natural variant	105	1	F → L in AD3. Ref.66		VAR_009208
	Natural variant	113	1	L → P in frontotemporal dementia. Ref.69		VAR_016215
	Natural variant	115	1	Y → C in AD3. Ref.52		VAR_006416
	Natural variant	115	1	Y → H in AD3. Ref.42 Ref.59		VAR_006417
	Natural variant	116	1	T → N in AD3. Ref.65		VAR_010120
	Natural variant	117	1	P → L in AD3. Ref.56		VAR_009209
	Natural variant	120	1	E → D in AD3. Ref.53 Ref.59		VAR_006418
	Natural variant	120	1	E → K in AD3.		VAR_006419
	Natural variant	135	1	N → D in AD3. Ref.46		VAR_010121
	Natural variant	139	1	M → I in AD3.		VAR_006420
	Natural variant	139	1	M → K in AD3. Ref.55		VAR_010122
	Natural variant	139	1	M → T in AD3. Ref.42 Ref.59		VAR_006421
	Natural variant	139	1	M → V in AD3. Ref.44 Ref.66		VAR_006422
	Natural variant	143	1	I → F in AD3. Ref.60		VAR_006423
	Natural variant	143	1	I → T in AD3. Ref.41		VAR_006424
	Natural variant	146	1	M → I in AD3.		VAR_006425
	Natural variant	146	1	M → L in AD3. Ref.1 Ref.59		VAR_006426
	Natural variant	146	1	M → V in AD3. Ref.44		VAR_006427
	Natural variant	147	1	T → I in AD3. Ref.59		VAR_010123
	Natural variant	163	1	H → R in AD3. Ref.1 Ref.42 Ref.45 Ref.53 Ref.59		VAR_006428
	Natural variant	163	1	H → Y in AD3. Ref.44		VAR_006429
	Natural variant	165	1	W → C in AD3. Ref.59		VAR_010124
	Natural variant	166	1	L → P in AD3; onset in adolescence. Ref.73		VAR_016216
	Natural variant	169	1	S → L in AD3. Ref.57		VAR_006430
	Natural variant	169	1	S → P in AD3. Ref.63		VAR_006431
	Natural variant	171	1	L → P in AD3. Ref.49		VAR_006432
	Natural variant	173	1	L → W in AD3. Ref.59		VAR_010125
	Natural variant	174	1	L → M in AD3. Ref.74		VAR_016217
	Natural variant	205	1	F → L: dbSNP rs1042864.		VAR_011876
	Natural variant	206	1	G → A in AD3. Ref.71		VAR_016218
	Natural variant	209	1	G → R in AD3. Ref.61		VAR_009210
	Natural variant	209	1	G → V in AD3. Ref.53		VAR_006433
	Natural variant	213	1	I → T in AD3. Ref.45		VAR_006434
	Natural variant	219	1	L → P in AD3. Ref.64		VAR_010126
	Natural variant	231	1	A → T in AD3. Ref.42 Ref.59		VAR_006435
	Natural variant	231	1	A → V in AD3. Ref.52		VAR_006436
	Natural variant	233	1	M → L in AD3. Ref.62		VAR_009211
	Natural variant	233	1	M → T in AD3. Ref.48 Ref.59		VAR_006437
	Natural variant	235	1	L → P in A3D. Ref.59		VAR_006438
	Natural variant	246	1	A → E in AD3. Ref.1		VAR_006439
	Natural variant	250	1	L → S in AD3.		VAR_006440
	Natural variant	260	1	A → V in AD3. Ref.43 Ref.53		VAR_006441
	Natural variant	262	1	L → F in AD3.		VAR_006442
	Natural variant	263	1	C → R in AD3.		VAR_006443
	Natural variant	264	1	P → L in AD3. Ref.42 Ref.53 Ref.59		VAR_006444
	Natural variant	266	1	G → S in AD3. Ref.72		VAR_016219
	Natural variant	267	1	P → S in AD3.		VAR_006445
	Natural variant	267	1	P → T in AD3. Ref.44		VAR_006446
	Natural variant	269	1	R → G in AD3.		VAR_006447
	Natural variant	269	1	R → H in AD3.		VAR_006448
	Natural variant	271	1	L → V in AD3. Ref.75		VAR_016220
	Natural variant	278	1	R → T in AD3. Ref.48		VAR_006449
	Natural variant	280	1	E → A in AD3. Ref.44 Ref.47		VAR_006450
	Natural variant	280	1	E → G in AD3. Ref.44		VAR_006451
	Natural variant	282	1	L → R in AD3. Ref.62		VAR_009212
	Natural variant	285	1	A → V in AD3. Ref.43		VAR_006452
	Natural variant	286	1	L → V in AD3. Ref.1		VAR_006453
	Natural variant	289	1	S → C in AD3.		VAR_010127
	Natural variant	318	1	E → G: dbSNP rs17125721. Ref.52 Ref.59 Ref.62 Ref.66 Ref.50 Ref.51 Ref.58 Ref.76		VAR_006454
	Natural variant	378	1	G → E in AD3. Ref.54		VAR_006455
	Natural variant	384	1	G → A in AD3. Ref.41		VAR_006456
	Natural variant	390	1	S → I in AD3. Ref.59		VAR_010128
	Natural variant	392	1	L → V in AD3. Ref.42 Ref.43 Ref.59		VAR_006457
	Natural variant	405	1	N → S in AD3. Ref.67		VAR_010129
	Natural variant	409	1	A → T in AD3. Ref.62		VAR_009213
	Natural variant	410	1	C → Y in AD3. Ref.42 Ref.53 Ref.59		VAR_006458
	Natural variant	426	1	A → P in AD3. Ref.53		VAR_006459
	Natural variant	431	1	A → E in AD3. Ref.70		VAR_025605
	Natural variant	436	1	P → Q in AD3. Ref.57		VAR_006460
	Natural variant	436	1	P → S in AD3. Ref.60		VAR_008141
Experimental info
	Mutagenesis	66 – 72	7	Missing: No effect on interaction with GFAP.
	Mutagenesis	76 – 77	2	KY → AA: No effect on interaction with GFAP.
	Mutagenesis	82 – 83	2	VI → EE: Loss of interaction with GFAP. Ref.28
	Mutagenesis	82	1	V → K or E: Loss of interaction with GFAP. Ref.28
	Mutagenesis	84 – 85	2	ML → EE: Loss of interaction with GFAP.
	Mutagenesis	256	1	Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. Ref.34
	Mutagenesis	257	1	D → A: Loss of endoproteolytic cleavage; reduces production of amyloid beta in APP processing and of NICD in NOTCH1 processing. Ref.22 Ref.23 Ref.34
	Mutagenesis	257	1	D → E: Abolishes gamma-secretase activity. Reduces production of amyloid beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor. Ref.22 Ref.23 Ref.34
	Mutagenesis	286	1	L → A, E, P, Q, R or W: Increases production of amyloid beta in APP processing. Ref.24
	Mutagenesis	286	1	L → E or R: Reduces production of NICD in NOTCH1 processing. Ref.24
	Mutagenesis	292	1	M → D: Loss of endoproteolytic cleavage. Ref.17
	Mutagenesis	310	1	S → A: Abolishes PKA-mediated phosphorylation; no effect on caspase-mediated cleavage. Ref.33
	Mutagenesis	345	1	D → N: Abolishes caspase cleavage. Ref.14
	Mutagenesis	346	1	S → A: Abolishes PKC-mediated phosphorylation; no effect on PKA-mediated phosphorylation. Ref.33
	Mutagenesis	346	1	S → E: Inhibits caspase-mediated cleavage. Modulates progression of apoptosis. Ref.33
	Mutagenesis	373	1	D → N: No effect on caspase cleavage. Ref.14
	Mutagenesis	385	1	D → A: Loss of endoproteolytic cleavage. Reduces production of amyloid beta in APP processing. Disassembly of the N-cadherin/PS1 complex at the cell surface. Impairs CDH2 processing. Ref.22 Ref.23 Ref.34 Ref.29 Ref.14
	Mutagenesis	385	1	D → E: Abolishes gamma-secretase activity. Reduces production of amyloid beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor. Ref.22 Ref.23 Ref.34 Ref.29 Ref.14
	Mutagenesis	385	1	D → N: No effect on caspase cleavage. Ref.22 Ref.23 Ref.34 Ref.29 Ref.14
	Mutagenesis	389	1	Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. Ref.34
	Mutagenesis	433	1	P → A: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased Abeta42/Abeta40 ratio. Ref.37
	Mutagenesis	433	1	P → D, F, L, N or V: No endoproteolytic cleavage; no APP nor NOTCH1 processing. No detectable Abetano detectable Abeta. Ref.37
	Mutagenesis	433	1	P → G: Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels Abeta40 and no detectable Abeta42. Ref.37
	Mutagenesis	434	1	A → C: Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. Six-fold increase in Abeta42/Abeta40 ratio. Ref.37
	Mutagenesis	434	1	A → D, I, L or V: No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta. Ref.37
	Mutagenesis	434	1	A → G: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Reduced Abeta42/Abeta40 ratio. Ref.37
	Mutagenesis	435	1	L → A: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced Abeta42/Abeta40 ratio. Ref.37
	Mutagenesis	435	1	L → F: No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta. Ref.37
	Mutagenesis	435	1	L → G: Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of Abeta40 and no detectable Abeta42. Ref.37
	Mutagenesis	435	1	L → I: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Ref.37
	Mutagenesis	435	1	L → V: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in Abeta42/Abeta40 ratio. Ref.37
	Sequence conflict	128	1	R → G in AAL16811. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (I-467) [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 5E0F451EF82BCF20	FASTA	467	52,668
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR 70 80 90 100 110 120 QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE 130 140 150 160 170 180 DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI 190 200 210 220 230 240 YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY 250 260 270 280 290 300 LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE 310 320 330 340 350 360 GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA 370 380 390 400 410 420 VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL 430 440 450 460 TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI
	Isoform 2 (I-463). Checksum: 955325791A81470F	FASTA	463	52,197
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTNDNRE RQEHNDRRSL GHPEPLSNGR PQGNSRQVVE 70 80 90 100 110 120 QDEEEDEELT LKYGAKHVIM LFVPVTLCMV VVVATIKSVS FYTRKDGQLI YTPFTEDTET 130 140 150 160 170 180 VGQRALHSIL NAAIMISVIV VMTILLVVLY KYRCYKVIHA WLIISSLLLL FFFSFIYLGE 190 200 210 220 230 240 VFKTYNVAVD YITVALLIWN FGVVGMISIH WKGPLRLQQA YLIMISALMA LVFIKYLPEW 250 260 270 280 290 300 TAWLILAVIS VYDLVAVLCP KGPLRMLVET AQERNETLFP ALIYSSTMVW LVNMAEGDPE 310 320 330 340 350 360 AQRRVSKNSK YNAESTERES QDTVAENDDG GFSEEWEAQR DSHLGPHRST PESRAAVQEL 370 380 390 400 410 420 SSSILAGEDP EERGVKLGLG DFIFYSVLVG KASATASGDW NTTIACFVAI LIGLCLTLLL 430 440 450 460 LAIFKKALPA LPISITFGLV FYFATDYLVQ PFMDQLAFHQ FYI
	Isoform 3 (I-374). Checksum: 5172C076410745BF	FASTA	374	42,287
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTNDNRE RQEHNDRRSL GHPEPLSNGR PQGNSRQVVE 70 80 90 100 110 120 QDEEEDEELT LKYGAKHVIM LFVPVTLCMV VVVATIKSVS FYTRKDGQLI YTPFTEDTET 130 140 150 160 170 180 VGQRALHSIL NAAIMISVIV VMTILLVVLY KYRCYKVIHA WLIISSLLLL FFFSFIYLGE 190 200 210 220 230 240 VFKTYNVAVD YITVALLIWN FGVVGMISIH WKGPLRLQQA YLIMISALMA LVFIKYLPEW 250 260 270 280 290 300 TAWLILAVIS VYDLVAVLCP KGPLRMLVET AQERNETLFP ALIYSSTMVW LVNMAEGDPE 310 320 330 340 350 360 AQRRVSKNSK YNAERACLPP AAINLLSIAP MAPRLFMPKG ACRPTAQKGS HKTLLQRMMM 370 AGSVRNGKPR GTVI
	Isoform 4 (Minilin). Checksum: 95C68A7EA0020874	FASTA	184	21,073
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR 70 80 90 100 110 120 QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE 130 140 150 160 170 180 DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VSMRHRSLLS TLFFLWLGIL VTVT
	Isoform 5. Checksum: A09D682EC6F568FD	FASTA	378	42,757
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR 70 80 90 100 110 120 QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE 130 140 150 160 170 180 DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI 190 200 210 220 230 240 YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY 250 260 270 280 290 300 LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE 310 320 330 340 350 360 GDPEAQRRVS KNSKYNAERA CLPPAAINLL SIAPMAPRLF MPKGACRPTA QKGSHKTLLQ 370 RMMMAGSVRN GKPRGTVI
	Isoform 6. Checksum: 4855BDDCCD1D7D71	FASTA	409	46,328
	10 20 30 40 50 60 MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR 70 80 90 100 110 120 QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE 130 140 150 160 170 180 DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI 190 200 210 220 230 240 YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY 250 260 270 280 290 300 LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE 310 320 330 340 350 360 GDPEAQRRVS KNSKYNAERG VKLGLGDFIF YSVLVGKASA TASGDWNTTI ACFVAILIGL 370 380 390 400 CLTLLLLAIF KKALPALPIS ITFGLVFYFA TDYLVQPFMD QLAFHQFYI

References

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[2]	"Identification and characterization of presenilin I-467, I-463 and I-374." Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M., Shirasawa T., Mori H. FEBS Lett. 381:7-11(1996) [PubMed: 8641442] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3). Tissue: Blood and Brain.
[3]	"Human presenilin 1 gene encodes an alternative protein-minilin." Powell C.S., Gegg M.E., Palmer M.S. Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
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[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Skin.
[8]	"Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential expression in oogenesis and embryogenesis." Tsujimura A., Yasojima K., Hashimoto-Gotoh T. Biochem. Biophys. Res. Commun. 231:392-396(1997) [PubMed: 9070286] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113.
[9]	"Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. Identification of a novel splice variant." Vidal R., Ghiso J., Wisniewski T., Frangione B. FEBS Lett. 393:19-23(1996) [PubMed: 8804415] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 24-32; 254-255; 290-292; 316-317 AND 376-379 (ISOFORM 6). Tissue: Megakaryocyte and Platelet.
[10]	"Purification and characterization of the human gamma-secretase complex." Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J., Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S. Biochemistry 43:9774-9789(2004) [PubMed: 15274632] [Abstract] Cited for: PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320; 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY, CHARACTERIZATION OF GAMMA-SECRETASE COMPLEX.
[11]	"Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells." Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E., Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., Tanzi R.E., Wasco W. Nat. Med. 2:224-229(1996) [PubMed: 8574969] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[12]	"Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue." Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J., Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P., St George-Hyslop P.H., Teplow D.B., Selkoe D.J. Neurobiol. Dis. 3:325-337(1997) [PubMed: 9173929] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[13]	"Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C." Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M., Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C. Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997) [PubMed: 9144240] [Abstract] Cited for: PHOSPHORYLATION.
[14]	"Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family." Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C. Biochemistry 37:2263-2270(1998) [PubMed: 9485372] [Abstract] Cited for: CASPASE CLEAVAGE SITE, MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385.
[15]	"Direct association of presenilin-1 with beta-catenin." Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X., Yasutake K., Nihonmatsu N., Wolozin B., Takashima A. FEBS Lett. 433:73-77(1998) [PubMed: 9738936] [Abstract] Cited for: INTERACTION WITH CTNNB1, SUBCELLULAR LOCATION.
[16]	"Interaction of presenilins with the filamin family of actin-binding proteins." Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y. J. Neurosci. 18:914-922(1998) [PubMed: 9437013] [Abstract] Cited for: INTERACTION WITH FLNA AND FLNB.
[17]	"Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis." Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M., Loetscher H., Jacobsen H., Haass C. Biochemistry 38:14600-14605(1999) [PubMed: 10545183] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF MET-292.
[18]	"Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1." Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z. J. Biol. Chem. 274:32543-32546(1999) [PubMed: 10551805] [Abstract] Cited for: INTERACTION WITH MTCH1.
[19]	"Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch." Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M., Selkoe D.J., Kopan R., Goate A.M. J. Biol. Chem. 274:36801-36807(1999) [PubMed: 10593990] [Abstract] Cited for: FUNCTION.
[20]	"Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and beta-catenin." Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D., Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L., VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E., St George-Hyslop P.H. J. Neurochem. 72:999-1008(1999) [PubMed: 10037471] [Abstract] Cited for: INTERACTION WITH CTNND2.
[21]	"Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts." Georgakopoulos A., Marambaud P., Efthimiopoulos S., Shioi J., Cui W., Li H.-C., Schutte M., Gordon R., Holstein G.R., Martinelli G., Mehta P., Friedrich V.L. Jr., Robakis N.K. Mol. Cell 4:893-902(1999) [PubMed: 10635315] [Abstract] Cited for: COMPONENT OF THE PSEN1/E-CADHERIN/CATENIN ADHESION COMPLEX WITH PSEN1; CDH1; CTNNA1 AND CTNNB1/CTNND1.
[22]	"Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity." Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T., Selkoe D.J. Nature 398:513-517(1999) [PubMed: 10206644] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-257 AND ASP-385.
[23]	"Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling." Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W., Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T. J. Neurochem. 75:583-593(2000) [PubMed: 10899933] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ASP-257 AND ASP-385.
[24]	"Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch." Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H., Capell A., Steiner H., Haass C. Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000) [PubMed: 10811883] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF LEU-286.
[25]	"Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex." Baki L., Marambaud P., Efthimiopoulos S., Georgakopoulos A., Wen P., Cui W., Shioi J., Koo E., Ozawa M., Friedrich V.L., Robakis N.K. Proc. Natl. Acad. Sci. U.S.A. 98:2381-2386(2001) [PubMed: 11226248] [Abstract] Cited for: FUNCTION, INTERACTION WITH CDH1.
[26]	"Identification of the presenilins in hematopoietic cells with localization of presenilin 1 to neutrophil and platelet granules." Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L., Rothermund K., Sisodia S.S., Borregaard N., Corey S.J. Blood Cells Mol. Dis. 28:28-38(2002) [PubMed: 11987239] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[27]	"Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein." Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R., Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B., Yanagisawa K., Komano H. J. Biol. Chem. 277:12915-12920(2002) [PubMed: 11799129] [Abstract] Cited for: INTERACTION WITH HERPUD1.
[28]	"A new splice variant of glial fibrillary acidic protein GFAPepsilon, interacts with the presenilin proteins." Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P., Jorgensen A.L. J. Biol. Chem. 277:29983-29991(2002) [PubMed: 12058025] [Abstract] Cited for: INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77; 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, CHARACTERIZATION OF VARIANTS AD3 VAL-79 AND LEU-82.
[29]	"Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane." Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K., Shibasaki H., Shimohama S. J. Neurosci. Res. 74:184-191(2003) [PubMed: 14515347] [Abstract] Cited for: INTERACTION WITH CDH2, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-385.
[30]	"Reconstitution of gamma-secretase activity." Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C. Nat. Cell Biol. 5:486-488(2003) [PubMed: 12679784] [Abstract] Cited for: ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX.
[31]	"Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2." Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S., Selkoe D.J. Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003) [PubMed: 12740439] [Abstract] Cited for: COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN.
[32]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004) [PubMed: 14759258] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[33]	"Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis." Fluhrer R., Friedlein A., Haass C., Walter J. J. Biol. Chem. 279:1585-1593(2004) [PubMed: 14576165] [Abstract] Cited for: PHOSPHORYLATION AT SER-310 AND SER-346, MUTAGENESIS OF SER-310 AND SER-346.
[34]	"Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding." Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A., De Strooper B., Shearman M.S., Beher D. J. Neurochem. 90:1312-1320(2004) [PubMed: 15341515] [Abstract] Cited for: FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, MUTAGENESIS OF TYR-256; ASP-257; ASP-385 AND TYR-389.
[35]	"Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability." Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J., Robakis N.K. J. Biol. Chem. 280:36007-36012(2005) [PubMed: 16126725] [Abstract] Cited for: INTERACTION WITH CDH1.
[36]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, MASS SPECTROMETRY. Tissue: Epithelium.
[37]	"C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation." Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A. J. Neurochem. 96:218-227(2006) [PubMed: 16305624] [Abstract] Cited for: FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435.
[38]	"The presenilin genes: a new gene family involved in Alzheimer disease pathology." Cruts M., Hendriks L., Van Broeckhoven C. Hum. Mol. Genet. 5:1449-1455(1996) [PubMed: 8875251] [Abstract] Cited for: REVIEW ON VARIANTS.
[39]	"Presenilin mutations in Alzheimer's disease." Cruts M., van Broeckhoven C. Hum. Mutat. 11:183-190(1998) [PubMed: 9521418] [Abstract] Cited for: REVIEW ON VARIANTS.
[40]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43; SER-365 AND SER-367, MASS SPECTROMETRY.
[41]	"Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3." Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J., de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M., Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L., Van Broeckhoven C. Hum. Mol. Genet. 4:2363-2372(1995) [PubMed: 8634711] [Abstract] Cited for: VARIANTS AD3 THR-143 AND ALA-384.
[42]	"Mutations of the presenilin I gene in families with early-onset Alzheimer's disease." Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C., Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M., Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M. , Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T. Hum. Mol. Genet. 4:2373-2377(1995) [PubMed: 8634712] [Abstract] Cited for: VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392 AND TYR-410.
[43]	"Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene." Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B., Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L. , Fraser P.E., Rommens J.M., St George-Hyslop P.H. Nature 376:775-778(1995) [PubMed: 7651536] [Abstract] Cited for: VARIANTS AD3 VAL-260; VAL-285 AND VAL-392.
[44]	"The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families." Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C., Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A., Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J. , Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J., Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L., Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R., Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L., Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B., Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D., Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D., Hardy J., Goate A.M. Nat. Genet. 11:219-222(1995) [PubMed: 7550356] [Abstract] Cited for: VARIANTS AD3 VAL-139; VAL-146; TYR-163; THR-267; ALA-280 AND GLY-280.
[45]	"Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families." Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H., Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T. Neurosci. Lett. 208:195-198(1996) [PubMed: 8733303] [Abstract] Cited for: VARIANTS AD3 PHE-96; ARG-163 AND THR-213.
[46]	"Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation." Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M., Hutton M., Haltia T., Hardy J., Galasko D. Ann. Neurol. 42:124-128(1997) [PubMed: 9225696] [Abstract] Cited for: VARIANT AD3 ASP-135.
[47]	"E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles." Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J., Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C., Ossa J., Ruiz A., Goate A.M., Lopera F. Hum. Mutat. 10:186-195(1997) [PubMed: 9298817] [Abstract] Cited for: VARIANT AD3 ALA-280.
[48]	"Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype." Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A., Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H., Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E., Schofield P.R., Martins R.N. NeuroReport 8:1537-1542(1997) [PubMed: 9172170] [Abstract] Cited for: VARIANTS AD3 THR-233 AND THR-278.
[49]	"A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease." Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C., Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H., Cantu J.M. Ann. Genet. 41:149-153(1998) [PubMed: 9833068] [Abstract] Cited for: VARIANT AD3 PRO-171.
[50]	"The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease." Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M., Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L. Ann. Neurol. 44:965-967(1998) [PubMed: 9851443] [Abstract] Cited for: VARIANT GLY-318.
[51]	"Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism." Aldudo J., Bullido M.J., Frank A., Valdivieso F. Ann. Neurol. 44:985-986(1998) [PubMed: 9851450] [Abstract] Cited for: VARIANT GLY-318.
[52]	"Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease." Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A., Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H., Hofman A., van Broeckhoven C. Hum. Mol. Genet. 7:43-51(1998) [PubMed: 9384602] [Abstract] Cited for: VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, VARIANT GLY-318.
[53]	"Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene." Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H., White J., Heston L., Bird T.D., Schellenberg G.D. Hum. Mutat. 11:216-221(1998) [PubMed: 9521423] [Abstract] Cited for: VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND PRO-426.
[54]	"Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification." Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E., Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A. Hum. Mutat. 11:481-481(1998) [PubMed: 10200054] [Abstract] Cited for: VARIANT AD3 GLU-378.
[55]	"De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases." Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V., Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T. J. Med. Genet. 35:672-673(1998) [PubMed: 9719376] [Abstract] Cited for: VARIANT AD3 LYS-139.
[56]	"A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years." Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S., Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B. NeuroReport 9:217-221(1998) [PubMed: 9507958] [Abstract] Cited for: VARIANT AD3 LEU-117.
[57]	"Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease." Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M., Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R., Martins R.N. NeuroReport 9:3335-3339(1998) [PubMed: 9831473] [Abstract] Cited for: VARIANTS AD3 LEU-169 AND GLN-436.
[58]	"The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease." Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C., Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A., van Duijn C.M., van Broeckhoven C. Am. J. Hum. Genet. 64:290-292(1999) [PubMed: 9915968] [Abstract] Cited for: VARIANT GLY-318.
[59]	"Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum." Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M., Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G., Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F., Brice A., Frebourg T. Am. J. Hum. Genet. 65:664-670(1999) [PubMed: 10441572] [Abstract] Cited for: VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163; CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND TYR-410, VARIANT GLY-318.
[60]	"Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset Alzheimer's disease in the UK." Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K., Fox N.C., Harvey R., Rossor M.N., Collinge J. Hum. Mutat. 13:256-256(1999) [PubMed: 10090481] [Abstract] Cited for: VARIANTS AD3 PHE-143 AND SER-436.
[61]	"A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease." Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y., Iseki E., Kosaka K. Hum. Mutat. 14:90-90(1999) [PubMed: 10447269] [Abstract] Cited for: VARIANT AD3 ARG-209.
[62]	"DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations." Aldudo J., Bullido M.J., Valdivieso F. Hum. Mutat. 14:433-439(1999) [PubMed: 10533070] [Abstract] Cited for: VARIANTS AD3 LEU-233; ARG-282 AND THR-409, VARIANT GLY-318.
[63]	"A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures." Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R. Neurology 52:566-570(1999) [PubMed: 10025789] [Abstract] Cited for: VARIANT AD3 PRO-169.
[64]	"Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene." Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K., Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L. NeuroReport 10:503-507(1999) [PubMed: 10208579] [Abstract] Cited for: VARIANT AD3 PRO-219.
[65]	"A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease." Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D., Havsager A.-M., Joergensen A.L. NeuroReport 10:2255-2260(1999) [PubMed: 10439444] [Abstract] Cited for: VARIANT AD3 ASN-116.
[66]	"High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes." Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J., Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A. Am. J. Hum. Genet. 66:110-117(2000) [PubMed: 10631141] [Abstract] Cited for: VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, VARIANT GLY-318.
[67]	"Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy." Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S., Maeda K., Tanaka C. J. Neurol. Neurosurg. Psych. 68:220-223(2000) [PubMed: 10644793] [Abstract] Cited for: VARIANT AD3 SER-405.
[68]	"The presenilin 1 C92S mutation increases abeta 42 production." Lewis P.A., Perez-Tur J., Golde T.E., Hardy J. Biochem. Biophys. Res. Commun. 277:261-263(2000) [PubMed: 11027672] [Abstract] Cited for: VARIANT AD3 SER-92.
[69]	"Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation." Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P., Hannequin D., Brice A., Frebourg T., Campion D. Neurology 55:1577-1578(2000) [PubMed: 11094121] [Abstract] Cited for: VARIANT FRONTOTEMPORAL DEMENTIA PRO-113.
[70]	Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J. Hum. Genet. 109:242-242(2001) Cited for: VARIANT AD3 GLU-431.
[71]	"A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families." Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H., Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E., Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K. , Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R. JAMA 286:2257-2263(2001) [PubMed: 11710891] [Abstract] Cited for: VARIANT AD3 ALA-206.
[72]	"Molecular evidence of presenilin 1 mutation in familial early onset dementia." Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K., Kohara K., Miyoshi K., Miki T. Am. J. Med. Genet. 114:292-298(2002) [PubMed: 11920851] [Abstract] Cited for: VARIANT AD3 SER-266.
[73]	"Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production." Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A., Kaether C., Zheng H., Ghetti B., Haass C., Steiner H. Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002) [PubMed: 12048239] [Abstract] Cited for: VARIANT AD3 PRO-166.
[74]	"A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease." Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J., Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M., van Duijn C.M., Heredero Baute L., Heutink P. Neurogenetics 4:97-104(2002) [PubMed: 12484344] [Abstract] Cited for: VARIANT AD3 MET-174.
[75]	"Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy." Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O., Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A., Gandy S.E., Schofield P.R. J. Biol. Chem. 278:6748-6754(2003) [PubMed: 12493737] [Abstract] Cited for: VARIANT AD3 VAL-271.
[76]	"Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome." Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F., Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J., Emans J.B., Turnpenny P.D., Pourquie O. Am. J. Hum. Genet. 82:1334-1341(2008) [PubMed: 18485326] [Abstract] Cited for: VARIANT GLY-318.
+	Additional computationally mapped references.

Web resources

Alzheimer Research Forum

Presenilins mutations

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	L42110 mRNA. Translation: AAB46416.1. L76517 mRNA. Translation: AAB46370.1. L76528 , L76519, L76520, L76521, L76522, L76523, L76524, L76525, L76526, L76527 Genomic DNA. Translation: AAB46371.1. U40379 mRNA. Translation: AAB05894.1. U40380 mRNA. Translation: AAB05895.1. AJ008005 mRNA. Translation: CAA07825.1. AF109907 Genomic DNA. Translation: AAC97960.1. AF416717 mRNA. Translation: AAL16811.1. AC004858 Genomic DNA. Translation: AAF19253.1. AC004858 Genomic DNA. Translation: AAF19254.1. BC011729 mRNA. Translation: AAH11729.1. D84149 Genomic DNA. Translation: BAA20883.1.
IPI	IPI00028077. IPI00068752. IPI00219934. IPI00289615. IPI00337671. IPI00514137.
PIR	S58396. S63683. S63684.
RefSeq	NP_000012.1. NP_015557.2.
UniGene	Hs.3260
3D structure databases
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:1134N.
IntAct	P49768. 10 interactions.
STRING	P49768.
Protein family/group databases
MEROPS	A22.001.
TCDB	1.A.54.1.1. presenilin ER Ca2+ leak channel (Presenilin) family.
PTM databases
PhosphoSite	P49768.
Proteomic databases
PRIDE	P49768.
Genome annotation databases
Ensembl	ENST00000261970; ENSP00000261970; ENSG00000080815; Homo sapiens. [Genome view] ENST00000324501; ENSP00000326366; ENSG00000080815; Homo sapiens. [Genome view] ENST00000344094; ENSP00000339523; ENSG00000080815; Homo sapiens. [Genome view] ENST00000357710; ENSP00000350342; ENSG00000080815; Homo sapiens. [Genome view] ENST00000394157; ENSP00000377712; ENSG00000080815; Homo sapiens. [Genome view] ENST00000394164; ENSP00000377719; ENSG00000080815; Homo sapiens. [Genome view] ENST00000406768; ENSP00000385948; ENSG00000080815; Homo sapiens. [Genome view]
GeneID	5663.
KEGG	hsa:5663.
UCSC	uc001xnq.2. human. uc001xnr.1. human. uc001xns.1. human.
Organism-specific databases
CTD	5663.
GeneCards	GC14P072672.
H-InvDB	HIX0011789.
HGNC	HGNC:9508. PSEN1.
HPA	CAB006844.
MIM	104311. gene. 600274. phenotype. 607822. phenotype.
Orphanet	1020. Alzheimer disease, familial. 154. Cardiomyopathy, familial dilated. 36385. Fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). 282. Frontotemporal dementia. 2883. Pick disease of brain.
PharmGKB	PA33855.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	P49768.
Enzyme and pathway databases
Pathway_Interaction_DB	p75ntrpathway. p75(NTR)-mediated signaling. ps1pathway. Presenilin action in Notch and Wnt signaling. syndecan_3_pathway. Syndecan-3-mediated signaling events.
Reactome	REACT_11061. Signalling by NGF. REACT_299. Signaling by Notch.
Gene expression databases
ArrayExpress	P49768.
Bgee	P49768.
CleanEx	HS_PSEN1.
Genevestigator	P49768.
GermOnline	ENSG00000080815. Homo sapiens.
Family and domain databases
InterPro	IPR002031. Pept_A22A_PS1. IPR006639. Peptidase_A22. IPR001108. Peptidase_A22A. [Graphical view]
PANTHER	PTHR10202:SF7. Pept_A22A_PS1. 1 hit. PTHR10202. Peptidase_A22A. 1 hit.
Pfam	PF01080. Presenilin. 1 hit. [Graphical view]
PRINTS	PR01072. PRESENILIN. PR01073. PRESENILIN1.
SMART	SM00730. PSN. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	22006.
PMAP-CutDB	P49768.
SOURCE	Search...

Entry information

Entry name

PSN1_HUMAN

Accession

Primary (citable) accession number: P49768
Secondary accession number(s): O95465 , Q14762, Q15719, Q15720, Q96P33, Q9UIF0

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	October 13, 2009
This is version 120 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.