Reviewed, UniProtKB/Swiss-Prot P29120 (NEC1_HUMAN)

Names and origin

Protein names

Recommended name:
    Neuroendocrine convertase 1
      Short name=NEC 1
    EC=3.4.21.93
Alternative name(s):
    Prohormone convertase 1
    Proprotein convertase 1
      Short name=PC1

Gene names

Name:	PCSK1
Synonyms:	NEC1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	753 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	Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin and insulin.
Catalytic activity	Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg-|- bonds.
Cofactor	Calcium.
Subcellular location	Cytoplasmic vesicle › secretory vesicle. Note: Localized in the secretion granules.
Polymorphism	Genetic variations in PCSK1 define the body mass index quantitative trait locus 12 (BMIQ12) [MIM:612362]. Variance in body mass index is a susceptibility factor for obesity.
Involvement in disease	Defects in PCSK1 are the cause of proprotein convertase 1 deficiency (PC1 deficiency) [MIM:600955]. PC1 deficiency is characterized by obesity, hypogonadism, hypoadrenalism, reactive hypoglycemia as well as marked small-intestinal absorptive dysfunction It is due to impaired processing of prohormones.
Sequence similarities	Belongs to the peptidase S8 family. Furin subfamily.

Ontologies

Keywords
Cellular component	Cytoplasmic vesicle
Coding sequence diversity	Polymorphism
Disease	Disease mutation Obesity
Domain	Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Zymogen
Gene Ontology (GO)
Uncategorized	proprotein convertase 1 activity Inferred from sequence or structural similarity. Source: UniProtKB
Biological process	cell-cell signaling Ref.5 Traceable author statement. Source: ProtInc peptide biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB proteolysis Ref.5 Traceable author statement. Source: ProtInc
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB secretory granule Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW serine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 27	27	Potential
	Propeptide	28 – 110	83	Potential		PRO_0000027057
	Chain	111 – 753	643	Neuroendocrine convertase 1		PRO_0000027058
Regions
	Region	122 – 410	289	Catalytic
	Region	739 – 751	13	Amphipathic Potential
Sites
	Active site	167	1	Charge relay system By similarity
	Active site	208	1	Charge relay system By similarity
	Active site	382	1	Charge relay system By similarity
Amino acid modifications
	Glycosylation	173	1	N-linked (GlcNAc...) Potential
	Glycosylation	401	1	N-linked (GlcNAc...) Potential
	Disulfide bond	225 ↔ 374		By similarity
	Disulfide bond	317 ↔ 347		By similarity
	Disulfide bond	467 ↔ 494		By similarity
Natural variations
	Natural variant	80	1	R → Q: dbSNP rs1799904. Ref.3		VAR_013906
	Natural variant	213	1	Missing in PC1 deficiency.		VAR_022777
	Natural variant	221	1	N → D Associated with susceptibility to obesity; induces a 10.4% reduction of activity (P = 0.03) when compared to the wild-type enzyme. dbSNP rs6232. Ref.6 Ref.10		VAR_013907
	Natural variant	307	1	S → L in PC1 deficiency; in vitro the mutation markedly impairs the catalytic activity of the enzyme; however intracellular trafficking of this mutant enzyme appears normal; retains some autocatalytic activity even though it is completely inactive on other substrates.		VAR_055002
	Natural variant	483	1	G → R in PC1 deficiency; prevents processing of pro-PCSK1 and leads to its retention in the endoplasmic reticulum.		VAR_022778
	Natural variant	665	1	Q → E: dbSNP rs6234. Ref.3 Ref.6 Ref.9		VAR_013908
	Natural variant	690	1	S → T: dbSNP rs6235. Ref.6 Ref.9		VAR_013909
Experimental info
	Sequence conflict	357	1	S → G in CAA46031. Ref.1
	Sequence conflict	370 – 371	2	LH → VD in BAA11133. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P29120-1 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: D3CBD1B92093A208	FASTA	753	84,152
	10 20 30 40 50 60 MERRAWSLQC TAFVLFCAWC ALNSAKAKRQ FVNEWAAEIP GGPEAASAIA EELGYDLLGQ 70 80 90 100 110 120 IGSLENHYLF KHKNHPRRSR RSAFHITKRL SDDDRVIWAE QQYEKERSKR SALRDSALNL 130 140 150 160 170 180 FNDPMWNQQW YLQDTRMTAA LPKLDLHVIP VWQKGITGKG VVITVLDDGL EWNHTDIYAN 190 200 210 220 230 240 YDPEASYDFN DNDHDPFPRY DPTNENKHGT RCAGEIAMQA NNHKCGVGVA YNSKVGGIRM 250 260 270 280 290 300 LDGIVTDAIE ASSIGFNPGH VDIYSASWGP NDDGKTVEGP GRLAQKAFEY GVKQGRQGKG 310 320 330 340 350 360 SIFVWASGNG GRQGDNCDCD GYTDSIYTIS ISSASQQGLS PWYAEKCSST LATSYSSGDY 370 380 390 400 410 420 TDQRITSADL HNDCTETHTG TSASAPLAAG IFALALEANP NLTWRDMQHL VVWTSEYDPL 430 440 450 460 470 480 ANNPGWKKNG AGLMVNSRFG FGLLNAKALV DLADPRTWRS VPEKKECVVK DNDFEPRALK 490 500 510 520 530 540 ANGEVIIEIP TRACEGQENA IKSLEHVQFE ATIEYSRRGD LHVTLTSAAG TSTVLLAERE 550 560 570 580 590 600 RDTSPNGFKN WDFMSVHTWG ENPIGTWTLR ITDMSGRIQN EGRIVNWKLI LHGTSSQPEH 610 620 630 640 650 660 MKQPRVYTSY NTVQNDRRGV EKMVDPGEEQ PTQENPKENT LVSKSPSSSS VGGRRDELEE 670 680 690 700 710 720 GAPSQAMLRL LQSAFSKNSP PKQSPKKSPS AKLNIPYENF YEALEKLNKP SQLKDSEDSL 730 740 750 YNDYVDVFYN TKPYKHRDDR LLQALVDILN EEN

References

[1]	"Expression in human lung tumor cells of the proprotein processing enzyme PC1/PC3. Cloning and primary sequence of a 5 kb cDNA." Creemers J.W.M., Roebroek A.J.M., van de Ven W.J.M. FEBS Lett. 300:82-88(1992) [PubMed: 1547893] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The cDNA sequence of the human pro-hormone and pro-protein convertase PC1." Seidah N.G., Hamelin J., Gaspar A.M., Day R., Chretien M. DNA Cell Biol. 11:283-289(1992) [PubMed: 1605851] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM." Ohagi S., Sakaguchi H., Sanke T., Tatsuta H., Hanabusa T., Nanjo K. Diabetes 45:897-901(1996) [PubMed: 8666140] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLN-80 AND GLU-665.
[4]	"Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements." Jansen E. J. Biol. Chem. 270:15391-15397(1995) [PubMed: 7797529] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-60.
[5]	"Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene." Jackson R.S., Creemers J.W., Ohagi S., Raffin-Sanson M.-L., Sanders L., Montague C.T., Hutton J.C., O'Rahilly S. Nat. Genet. 16:303-306(1997) [PubMed: 9207799] [Abstract] Cited for: VARIANT PC1 DEFICIENCY ARG-483.
[6]	"Characterization of single-nucleotide polymorphisms in coding regions of human genes." Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 22:231-238(1999) [PubMed: 10391209] [Abstract] Cited for: VARIANTS ASP-221; GLU-665 AND THR-690.
[7]	Erratum Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 23:373-373(1999)
[8]	"Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency." Jackson R.S., Creemers J.W., Farooqi I.S., Raffin-Sanson M.-L., Varro A., Dockray G.J., Holst J.J., Brubaker P.L., Corvol P., Polonsky K.S., Ostrega D., Becker K.L., Bertagna X., Hutton J.C., White A., Dattani M.T., Hussain K., Middleton S.J. , Nicole T.M., Milla P.J., Lindley K.J., O'Rahilly S. J. Clin. Invest. 112:1550-1560(2003) [PubMed: 14617756] [Abstract] Cited for: VARIANT PC1 DEFICIENCY ALA-213 DEL.
[9]	"Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3." Farooqi I.S., Volders K., Stanhope R., Heuschkel R., White A., Lank E., Keogh J., O'Rahilly S., Creemers J.W.M. J. Clin. Endocrinol. Metab. 92:3369-3373(2007) [PubMed: 17595246] [Abstract] Cited for: VARIANT PC1 DEFICIENCY LEU-307, CHARACTERIZATION OF VARIANT PC1 DEFICIENCY LEU-307, VARIANTS GLU-665 AND THR-690.
[10]	"Common nonsynonymous variants in PCSK1 confer risk of obesity." Benzinou M., Creemers J.W.M., Choquet H., Lobbens S., Dina C., Durand E., Guerardel A., Boutin P., Jouret B., Heude B., Balkau B., Tichet J., Marre M., Potoczna N., Horber F., Le Stunff C., Czernichow S., Sandbaek A. , Lauritzen T., Borch-Johnsen K., Andersen G., Kiess W., Koerner A., Kovacs P., Jacobson P., Carlsson L.M.S., Walley A.J., Joergensen T., Hansen T., Pedersen O., Meyre D., Froguel P. Nat. Genet. 40:943-945(2008) [PubMed: 18604207] [Abstract] Cited for: VARIANT ASP-221, CHARACTERIZATION OF VARIANT ASP-221, ASSOCIATION WITH SUSCEPTIBILITY TO OBESITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X64810 mRNA. Translation: CAA46031.1. M90753 mRNA. Translation: AAA59918.1. D73407 Genomic DNA. Translation: BAA11133.1. U24128 Genomic DNA. Translation: AAA73788.1.
IPI	IPI00301961.
PIR	KXHUC1. S21106.
RefSeq	NP_000430.3.
UniGene	Hs.78977
3D structure databases
HSSP	HSSP built from PDB template 1KN6 based on UniProtKB P21662.
ModBase	Search...
Protein family/group databases
MEROPS	S08.072.
Proteomic databases
PRIDE	P29120.
Genome annotation databases
Ensembl	ENSG00000175426. Homo sapiens. [Contig view]
GeneID	5122.
KEGG	hsa:5122.
Organism-specific databases
GeneCards	GC05M095751.
H-InvDB	HIX0024836.
HGNC	HGNC:8743. PCSK1.
MIM	162150. gene. 600955. phenotype. 612362. phenotype.
Orphanet	71528. Obesity due to prohormone convertase-I deficiency.
PharmGKB	PA33089.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P29120.
HOVERGEN	P29120.
OMA	P29120. HDPFPRY.
Enzyme and pathway databases
BRENDA	3.4.21.93. 247.
Gene expression databases
ArrayExpress	P29120.
Bgee	P29120.
CleanEx	HS_PCSK1.
GermOnline	ENSG00000175426. Homo sapiens.
Family and domain databases
InterPro	IPR000209. Pept_S8_S53. IPR015500. Peptidase_S8_subtilisin-rel. IPR002884. PrprotnconvertsP. [Graphical view]
Gene3D	G3DSA:3.40.50.200. Pept_S8_S53. 1 hit.
PANTHER	PTHR10795. SubtilSerProt. 1 hit.
Pfam	PF01483. P_proprotein. 1 hit. PF00082. Peptidase_S8. 1 hit. [Graphical view]
PRINTS	PR00723. SUBTILISIN.
ProDom	PD000717. PrprotnconvertsP. 1 hit. [Graphical view] [Entries sharing at least one domain]
PROSITE	PS00136. SUBTILASE_ASP. 1 hit. PS00137. SUBTILASE_HIS. 1 hit. PS00138. SUBTILASE_SER. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00047. Insulin Glargine recombinant. DB00046. Insulin Lyspro recombinant. DB00030. Insulin recombinant. DB00071. Insulin, porcine.
NextBio	19750.
PMAP-CutDB	P29120.
SOURCE	Search...

Entry information

Entry name

NEC1_HUMAN

Accession

Primary (citable) accession number: P29120
Secondary accession number(s): P78478, Q92532

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 1992
Last sequence update:	October 17, 2006
Last modified:	June 16, 2009
This is version 96 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)