Q8TCT6 (SPPL3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Signal peptide peptidase-like 3
Short name=SPP-like 3
EC=3.4.23.-

Alternative name(s):
Intramembrane protease 2
Short name=IMP-2
Presenilin homologous protein 1
Short name=PSH1
Presenilin-like protein 4

Gene names

Name:	SPPL3
Synonyms:	IMP2, PSL4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	385 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Ref.10
Enzyme regulation	Its proteolytic activity is blocked by signal peptide peptidase (SPP) inhibitors. Ref.10
Subunit structure	Monomer. Homodimer. Ref.10
Subcellular location	Membrane; Multi-pass membrane protein. Endoplasmic reticulum membrane; Multi-pass membrane protein. Note: Restricted to the early secretory compartment. Ref.9 Ref.11
Tissue specificity	Ubiquitous. Ref.8
Domain	The PAL motif is required for normal active site conformation By similarity. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP. The first transmembrane domain may act as a type I signal anchor.
Post-translational modification	Not glycosylated.
Sequence similarities	Belongs to the peptidase A22B family.
Sequence caution	The sequence BAC11290.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Alternative splicing
Domain	Transmembrane Transmembrane helix
Molecular function	Hydrolase Protease
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	Golgi-associated vesicle membrane Inferred from direct assay Ref.11. Source: UniProtKB integral to cytosolic side of endoplasmic reticulum membrane Inferred from direct assay Ref.8. Source: UniProtKB integral to lumenal side of endoplasmic reticulum membrane Inferred from direct assay Ref.8. Source: UniProtKB rough endoplasmic reticulum Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	aspartic endopeptidase activity, intramembrane cleaving Inferred from mutant phenotype Ref.10. Source: UniProtKB protein homodimerization activity Inferred from direct assay Ref.8Ref.9Ref.10. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Experimental confirmation may be lacking for some isoforms.

Isoform 1 (identifier: Q8TCT6-1)

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: Q8TCT6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     59-82: EQEPIIGFQPMDSTRARFLPMGAC → NSTNNSIQTIDSTQALFLPIGAS

Isoform 3 (identifier: Q8TCT6-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-216: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 385	385	Signal peptide peptidase-like 3		PRO_0000073912
Regions
	Topological domain	1 – 8	8	Lumenal Potential
	Transmembrane	9 – 29	21	Helical; Potential
	Topological domain	30 – 75	46	Cytoplasmic Potential
	Transmembrane	76 – 96	21	Helical; Potential
	Topological domain	97 – 98	2	Lumenal Potential
	Transmembrane	99 – 119	21	Helical; Potential
	Topological domain	120 – 137	18	Cytoplasmic Potential
	Transmembrane	138 – 160	23	Helical; Potential
	Topological domain	161 – 165	5	Lumenal Potential
	Transmembrane	166 – 186	21	Helical; Potential
	Topological domain	187 – 191	5	Cytoplasmic Potential
	Transmembrane	192 – 212	21	Helical; Potential
	Topological domain	213 – 263	51	Lumenal Potential
	Transmembrane	264 – 284	21	Helical; Potential
	Topological domain	285 – 312	28	Cytoplasmic Potential
	Transmembrane	313 – 333	21	Helical; Potential
	Topological domain	334 – 340	7	Lumenal Potential
	Transmembrane	341 – 361	21	Helical; Potential
	Topological domain	362 – 385	24	Cytoplasmic Potential
	Motif	342 – 344	3	PAL
	Compositional bias	375 – 380	6	Poly-Ser
Sites
	Active site	201	1	By similarity
	Active site	272	1	By similarity
Natural variations
	Alternative sequence	1 – 216	216	Missing in isoform 3.		VSP_005205
	Alternative sequence	59 – 82	24	EQEPI…PMGAC → NSTNNSIQTIDSTQALFLPI GAS in isoform 2.		VSP_005206
Experimental info
	Sequence conflict	140	1	F → Y in BAC11290. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 2002. Version 1. Checksum: BF829565E14A2996	FASTA	385	42,563
	10 20 30 40 50 60 MAEQTYSWAY SLVDSSQVST FLISILLIVY GSFRSLNMDF ENQDKEKDSN SSSGSFNGEQ 70 80 90 100 110 120 EPIIGFQPMD STRARFLPMG ACVSLLVMFF FFDSVQVVFT ICTAVLATIA FAFLLLPMCQ 130 140 150 160 170 180 YLTRPCSPQN KISFGCCGRF TAAELLSFSL SVMLVLIWVL TGHWLLMDAL AMGLCVAMIA 190 200 210 220 230 240 FVRLPSLKVS CLLLSGLLIY DVFWVFFSAY IFNSNVMVKV ATQPADNPLD VLSRKLHLGP 250 260 270 280 290 300 NVGRDVPRLS LPGKLVFPSS TGSHFSMLGI GDIVMPGLLL CFVLRYDNYK KQASGDSCGA 310 320 330 340 350 360 PGPANISGRM QKVSYFHCTL IGYFVGLLTA TVASRIHRAA QPALLYLVPF TLLPLLTMAY 370 380 LKGDLRRMWS EPFHSKSSSS RFLEV
	Isoform 2 [UniParc]. Checksum: 04D8C036355B32A1	FASTA	384	42,261
	10 20 30 40 50 60 MAEQTYSWAY SLVDSSQVST FLISILLIVY GSFRSLNMDF ENQDKEKDSN SSSGSFNGNS 70 80 90 100 110 120 TNNSIQTIDS TQALFLPIGA SVSLLVMFFF FDSVQVVFTI CTAVLATIAF AFLLLPMCQY 130 140 150 160 170 180 LTRPCSPQNK ISFGCCGRFT AAELLSFSLS VMLVLIWVLT GHWLLMDALA MGLCVAMIAF 190 200 210 220 230 240 VRLPSLKVSC LLLSGLLIYD VFWVFFSAYI FNSNVMVKVA TQPADNPLDV LSRKLHLGPN 250 260 270 280 290 300 VGRDVPRLSL PGKLVFPSST GSHFSMLGIG DIVMPGLLLC FVLRYDNYKK QASGDSCGAP 310 320 330 340 350 360 GPANISGRMQ KVSYFHCTLI GYFVGLLTAT VASRIHRAAQ PALLYLVPFT LLPLLTMAYL 370 380 KGDLRRMWSE PFHSKSSSSR FLEV
	Isoform 3 [UniParc]. Checksum: 7A97E2C1713CB938	FASTA	169	18,478
	10 20 30 40 50 60 MVKVATQPAD NPLDVLSRKL HLGPNVGRDV PRLSLPGKLV FPSSTGSHFS MLGIGDIVMP 70 80 90 100 110 120 GLLLCFVLRY DNYKKQASGD SCGAPGPANI SGRMQKVSYF HCTLIGYFVG LLTATVASRI 130 140 150 160 HRAAQPALLY LVPFTLLPLL TMAYLKGDLR RMWSEPFHSK SSSSRFLEV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of a new protein family with homology to presenilins." Irmler M., Tomiuk S., Korner M.R., Hofmann K., Conradt M. Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Identification of signal peptide peptidase, a presenilin-type aspartic protease." Weihofen A., Binns K., Lemberg M.K., Ashman K., Martoglio B. Science 296:2215-2218(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Cervix carcinoma.
[3]	"Novel class of polytopic proteins with domains associated with putative protease activity." Grigorenko A.P., Moliaka Y.K., Korovaitseva G.I., Rogaev E.I. Biokhimiia 67:826-834(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Blood.
[4]	"Proteolytic processing, N-glycosylation, and proteasomal degradation of human signal peptide peptidase-like protein 3: the YD and PAL motifs, but not the GXGD motif, are critical for protein stability." Kondo K., Heike T., Yorifuji T., Nishikomori R., Kawai M., Ma F., Ma L., Adachi S., Nakahata T. Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal brain.
[5]	Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). Tissue: Liver, Pancreas and Testis.
[7]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 12-385 (ISOFORM 2). Tissue: Teratocarcinoma.
[8]	"Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins." Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., Martoglio B. J. Biol. Chem. 279:50790-50798(2004) [PubMed] [Europe PMC] [Abstract] Cited for: TOPOLOGY, TISSUE SPECIFICITY.
[9]	"Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3." Krawitz P., Haffner C., Fluhrer R., Steiner H., Schmid B., Haass C. J. Biol. Chem. 280:39515-39523(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[10]	"Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase." Nyborg A.C., Ladd T.B., Jansen K., Kukar T., Golde T.E. FASEB J. 20:1671-1679(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, HOMODIMERIZATION.
[11]	"SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production." Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B. Nat. Cell Biol. 8:843-848(2006) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ345030 mRNA. Translation: CAC87791.1. AJ420898 mRNA. Translation: CAD13135.1. AY169313 mRNA. Translation: AAO12538.1. AB252457 mRNA. Translation: BAF30928.1. CH471054 Genomic DNA. Translation: EAW98220.1. BC009551 mRNA. Translation: AAH09551.1. BC025781 mRNA. Translation: AAH25781.1. BC073910 mRNA. Translation: AAH73910.1. BC101625 mRNA. Translation: AAI01626.1. BC101627 mRNA. Translation: AAI01628.1. AK074916 mRNA. Translation: BAC11290.1. Different initiation.
IPI	IPI00152440. IPI00220448. IPI00472181.
RefSeq	NP_620584.2. NM_139015.4.
UniGene	Hs.507087. Hs.683964.
3D structure databases
ModBase	Search...
Protein family/group databases
MEROPS	A22.005.
Polymorphism databases
DMDM	25008979.
Proteomic databases
PaxDb	Q8TCT6.
PRIDE	Q8TCT6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000353487; ENSP00000288680; ENSG00000157837.
GeneID	121665.
KEGG	hsa:121665.
UCSC	uc001tzc.3. human.
Organism-specific databases
CTD	121665.
GeneCards	GC12M121202.
HGNC	HGNC:30424. SPPL3.
MIM	608240. gene.
neXtProt	NX_Q8TCT6.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG250196.
HOGENOM	HOG000243413.
HOVERGEN	HBG023986.
InParanoid	Q8TCT6.
KO	K09598.
OMA	NYKKQAN.
OrthoDB	EOG4WSWB2.
Gene expression databases
Genevestigator	Q8TCT6.
GermOnline	ENSG00000157837. Homo sapiens.
Family and domain databases
InterPro	IPR006639. Peptidase_A22. IPR007369. Peptidase_A22B_SPP. [Graphical view]
PANTHER	PTHR12174. PTHR12174. 1 hit.
Pfam	PF04258. Peptidase_A22B. 1 hit. [Graphical view]
SMART	SM00730. PSN. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	SPPL3. human.
GenomeRNAi	121665.
NextBio	80798.
SOURCE	Search...

Entry information

Entry name

SPPL3_HUMAN

Accession

Primary (citable) accession number: Q8TCT6
Secondary accession number(s): Q3MJ04, Q8TAU4, Q96DD9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 8, 2002
Last sequence update:	June 1, 2002
Last modified:	April 3, 2013
This is version 98 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.