KEX2/YNL238W Summary Help

Standard Name KEX2 1
Systematic Name YNL238W
Alias QDS1 , VMA45 , SRB1 2
Feature Type ORF, Verified
Description Subtilisin-like protease (proprotein convertase), a calcium-dependent serine protease involved in the activation of proproteins of the secretory pathway (3 and see Summary Paragraph)
Name Description Killer EXpression defective
Gene Product Alias kexin , yscF 4
Chromosomal Location
ChrXIV:202428 to 204872 | ORF Map | GBrowse
Gbrowse
Genetic position: -147 cM
Gene Ontology Annotations All KEX2 GO evidence and references
  View Computational GO annotations for KEX2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Mutant phenotypes All KEX2 Phenotype evidence and references
Classical genetics
null
Large-scale survey
null
overexpression
Resources
interactions All KEX2 Interaction evidence and references
221 total interaction(s) for 142 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 6
  • Affinity Capture-RNA: 1
  • Affinity Capture-Western: 2
  • Biochemical Activity: 1
  • Co-fractionation: 1
  • Co-purification: 1
  • PCA: 11
  • Protein-peptide: 1
  • Protein-RNA: 1
  • Two-hybrid: 4
Genetic Interactions
  • Dosage Rescue: 19
  • Negative Genetic: 55
  • Phenotypic Enhancement: 38
  • Phenotypic Suppression: 16
  • Positive Genetic: 39
  • Synthetic Growth Defect: 6
  • Synthetic Haploinsufficiency: 1
  • Synthetic Lethality: 11
  • Synthetic Rescue: 7
Resources
Expression Summary
histogram
Resources
Protein Information All KEX2 Protein evidence and references
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXIV:202428 to 204872 | ORF Map | GBrowse
SGD ORF map
Genetic position: -147 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates		 Chromosomal
Coordinates		 Most Recent Updates
Coordinates Sequence
CDS 1..2445 202428..204872 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000005182
SUMMARY PARAGRAPH for KEX2

KEX2 encodes a Ca2+ dependent serine protease involved in proprotein processing (3, 5). Kex2p cleaves at paired dibasic sites in target peptides and is required to produce the mature forms of secreted proteins such as alpha-factor and killer toxin (6 and reviewed in 7). Kex2p is a membrane-bound protein that is initially targeted to the ER and ultimately functions at the trans-golgi network (TGN), cycling between trans-golgi vesicles and late endosomal compartments (8, ,9).

Kex2p is initially translated as an inactive precursor with multiple domains, some of which are eventually removed. The Kex2p zymogen contains an N-terminal ER signal peptide, followed by a pro-domain, a catalytic domain, a P-domain of unknown function that is conserved among proteases of this family and necessary for in vivo catalytic activity, a serine/threonine rich region that is hyper-glycosylated, a single transmembrane domain, and a cytosolic tail containing a TGN localization signal (10, 11, 12, 13 and references contained therein, and reviewed in 14). During Kex2p activation, the N-terminus of the protein undergoes a number of post-translational processing steps. First, the signal peptide is cleaved cotranslationally in the ER (8). Next the pro-domain, which functions both as a chaperone and a self-inhibitor, is removed through intramolecular, self-mediated cleavage thus activating the enzyme (15, 16, 17, 18). This is followed by additional N-terminal processing by the Ste13p dipeptidyl aminopeptidase in the Golgi, generating the mature form of Kex2p (19).

KEX2 is a member of a large family of proteases related to bacterial subtilisin (reviewed in 20). In the pathogenic yeast Candida albicans, the Kex2p homolog is a virulence factor (21). Eukaryotic homologs include furin (OMIM), PC1 (OMIM), PC2 (OMIM), and other proprotein convertases that are required for the processing of secreted hormones such as proinsulin, proglucagon, and neuropeptide precursors. Defects in these genes have been associated with diseases such as diabetes (OMIM) and cancer (reviewed in 22 and 23).

Last updated: 2006-04-25

References cited on this page View Complete Literature Guide for KEX2
1) Link, A. and Olson, M.  (1989) Personal Communication, Mortimer Map Edition 10
2) Martin C and Young RA  (1989) KEX2 mutations suppress RNA polymerase II mutants and alter the temperature range of yeast cell growth. Mol Cell Biol 9(6):2341-9
3) Fuller RS, et al.  (1989) Yeast prohormone processing enzyme (KEX2 gene product) is a Ca2+-dependent serine protease. Proc Natl Acad Sci U S A 86(5):1434-8
4) Seeboth PG and Heim J  (1991) In-vitro processing of yeast alpha-factor leader fusion proteins using a soluble yscF (Kex2) variant. Appl Microbiol Biotechnol 35(6):771-6
5) Fuller RS, et al.  (1989) Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science 246(4929):482-6
6) Julius D, et al.  (1984) Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell 37(3):1075-89
7) Fuller RS, et al.  (1988) Enzymes required for yeast prohormone processing. Annu Rev Physiol 50:345-62
8) Wilcox CA and Fuller RS  (1991) Posttranslational processing of the prohormone-cleaving Kex2 protease in the Saccharomyces cerevisiae secretory pathway. J Cell Biol 115(2):297-307
9) Bryant NJ and Stevens TH  (1997) Two separate signals act independently to localize a yeast late Golgi membrane protein through a combination of retrieval and retention. J Cell Biol 136(2):287-97
10) Gluschankof P and Fuller RS  (1994) A C-terminal domain conserved in precursor processing proteases is required for intramolecular N-terminal maturation of pro-Kex2 protease. EMBO J 13(10):2280-8
11) Wilcox CA, et al.  (1992) Mutation of a tyrosine localization signal in the cytosolic tail of yeast Kex2 protease disrupts Golgi retention and results in default transport to the vacuole. Mol Biol Cell 3(12):1353-71
12) Brickner JH and Fuller RS  (1997) SOI1 encodes a novel, conserved protein that promotes TGN-endosomal cycling of Kex2p and other membrane proteins by modulating the function of two TGN localization signals. J Cell Biol 139(1):23-36
13) Holyoak T, et al.  (2003) 2.4 A resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor. Biochemistry 42(22):6709-18
14) Rockwell NC and Thorner JW  (2004) The kindest cuts of all: crystal structures of Kex2 and furin reveal secrets of precursor processing. Trends Biochem Sci 29(2):80-7
15) Lesage G, et al.  (2000) The Kex2p proregion is essential for the biosynthesis of an active enzyme and requires a C-terminal basic residue for its function. Mol Biol Cell 11(6):1947-57
16) Lesage G, et al.  (2001) Mechanism of Kex2p inhibition by its proregion. FEBS Lett 508(3):332-6
17) Germain D, et al.  (1992) The pro-region of the Kex2 endoprotease of Saccharomyces cerevisiae is removed by self-processing. FEBS Lett 299(3):283-6
18) Germain D, et al.  (1993) Processing of Kex2 pro-region at two interchangeable cleavage sites. FEBS Lett 323(1-2):129-31
19) Brenner C and Fuller RS  (1992) Structural and enzymatic characterization of a purified prohormone-processing enzyme: secreted, soluble Kex2 protease. Proc Natl Acad Sci U S A 89(3):922-6
20) Brenner C  (2003) Subtleties among subtilases. The structural biology of Kex2 and furin-related prohormone convertases. EMBO Rep 4(10):937-8
21) Newport G, et al.  (2003) Inactivation of Kex2p diminishes the virulence of Candida albicans. J Biol Chem 278(3):1713-20
22) Zhou A, et al.  (1999) Proteolytic processing in the secretory pathway. J Biol Chem 274(30):20745-8
23) Bassi DE, et al.  (2005) Proprotein convertases: "master switches" in the regulation of tumor growth and progression. Mol Carcinog 44(3):151-61