Family P2

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

P2A

Summary Holotypes Alignment Tree Genomes Literature

P2B

Summary Holotypes Alignment Tree Genomes Literature

Summary for family P2

Family type peptidaseP02.001 - EGF-like module containing mucin-like hormone receptor-like 2 (Homo sapiens), MEROPS Accession MER0037230 (peptidase unit: 478-529)
Content of familyFamily P2 contains autolytic endopeptidases.
History Identifier created: MEROPS 10.0 (14 Mar 2016)
Formed by merging S63 and T6 which now form subfamilies P2A and P2B, respectively. Post-translational proteolytic cleavage is an essential step in the formation of the G protein-coupled receptor heterodimer. Cleavage occurs at the "G protein-coupled receptor proteolytic site" (GPS), but the mechanism of cleavage of the GPS has been obscure. Now, Lin et al. (2004) have shown that for the human epidermal growth factor-like module containing mucin-like hormone receptor 2 (EMR2) precursor (S63.001) intramolecular autolysis occurs in a reaction similar to that which occurs in the precursors of Ntn-hydrolases (see clan PB). Polycystin-1 is a large transmembrane protein that is important for renal tubule diameter control. One of the many domains is a GPS domain, which is extracellular but next to the first of eleven transmembrane regions. Polycystin-1 is coupled to a G protein. Cleavage occurs within the GPS domain, which is assumed to be important for signal transduction, and this has recently been shown to be by a cis-autolytic mechanism (Wei et al., 2007 ).
Catalytic typeMixed (C, S, T) catalytic type
Active siteThe active serine in the EMR2 precursor has been identified by site-directed mutagenesis (Lin et al., 2004). The authors also show that replacement of this residue with cysteine or threonine produces an active enzyme. In addition, His516 was shown to be important, and the authors suggest that it is the proton donor/acceptor for the generation of a tetrahedral intermediate. The catalytic Thr in polycystin-1 has also been indentified by site-directed mutagenesis. Cleavage still occurs if this is substituted with Ser or Cys (Wei et al., 2007 ).
Activities and specificitiesAutolysis in the human EMR2 precursor is at the Leu517Ser bond and occurs within a site known as GPS . The polycystin-1 precursor cleaves itself at the Leu3048Thr bond. Cleavage occurs in the endoplasmic reticulum or the Golgi (Wei et al., 2007 ).
InhibitorsProteolysis is unaffected by chelating agents such as EDTA, and inhibitors such as E-64, aprotinin (I02.001) and pepstatin (Lin et al. (2004)).
Molecular structureThe EMR2 precursor is one of a group of cell-surface proteins known as class B2 G protein-coupled receptors or the LNB-TM7 receptors. Members of this group have an N-terminal adhesion-like extracellular domain and a C-terminal secretin receptor-like domain. The extracellular domain contains five tandem repeats of the epidermal growth factor-like module, a Ser/Thr-rich stalk and the GPS. The C-terminal domain has seven transmembrane regions. The GPS motif is proximal to the first membrane spanning region. The Ser/Thr-rich stalk has been shown to be necessary for proteolysis to occur (Chang et al., 2003). No tertiary structure has been solved for any member of family P2, but because the active site residue is also the P1" residue in the autolytic cleavage, it is likely that family P2 is related to other N-terminal hydrolases in clan PB.
ClanPB
Distribution of family Bacteria -  
Archaea -  
Protozoa details  
Fungi -  
Plants -  
Animals details  
Viruses -  
Biological functionsCleavage of the human EMR2 precursor occurs within the endoplasmic reticulum. Cleavage releases the extracellular domain (the alpha subunit) which remains covalently attached to the membrane-bound domain (the beta subunit) to form a heterodimer. Processing is shown to be essential for normal biological activity by the fact that naturally- occurring mutations in the polycystin-1 precursor prevent processing and disrupt function.
Pharmaceutical and biotech relevanceDefects in the polycystin-1 gene results in kidney cyst formation known as human autosomal dominant polycystic kidney disease.
ReviewsThe article of Lin et al. (2004) is recommended.
Statistics for family P2Sequences:6282
Identifiers:48
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily P2A
Name Peptidase subfamily P2A
Subfamily type peptidase P02.001 - EGF-like module containing mucin-like hormone receptor-like 2 (Homo sapiens), MEROPS Accession MER0037230 (peptidase unit: 478-529)
Active site residues S518 
Statistics Sequences: 5752
Identifiers: 44
Identifiers with PDB entries: 3
Other databases INTERPRO IPR000203
PANTHER PTHR12011
PFAM PF00002
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
EGF-like module containing mucin-like hormone receptor-like 2P02.001-
CD97 antigen (human type)P02.002-
EGF-like module containing mucin-like hormone receptor-like 3P02.003-
EGF-like module containing mucin-like hormone receptor-like 1P02.004-
EGF-like module containing mucin-like hormone receptor-like 4P02.005-
cadherin EGF LAG seven-pass G-type receptor 2 precursor (Homo sapiens)P02.006-
Gpr64 (Mus musculus)-type proteinP02.007-
GPR56 (Homo sapiens)-type proteinP02.008-
latrophilin 2P02.009-
latrophilin-1P02.010Yes
latrophilin 3P02.011Yes
ETL proteinP02.013-
G protein-coupled receptor 112P02.014-
seven transmembrane helix receptorP02.015-
Gpr114 proteinP02.016-
GPR126 vascular inducible G protein-coupled receptorP02.017-
GPR125 (Homo sapiens)-type proteinP02.018-
GPR116 (Homo sapiens)-type G-protein coupled receptorP02.019-
GPR128 (Homo sapiens)-type G-protein coupled receptorP02.020-
GPR133 (Homo sapiens)-type proteinP02.021-
GPR110 G-protein coupled receptorP02.022-
GPR97 proteinP02.023-
KPG_006 proteinP02.024-
KPG_008 proteinP02.025-
KPG_009 proteinP02.026-
brain angiogenesis inhibitor 3P02.027Yes
GPR113 proteinP02.028-
brain-specific angiogenesis inhibitor 2P02.029-
brain-specific angiogenesis inhibitor 3 (Mus musculus)P02.030-
G protein-coupled receptor 128 (Mus musculus-type)P02.031-
G protein-coupled receptor 116P02.032-
CD97 antigen (mouse-type)P02.033-
mCG4533 protein (Mus musculus)P02.034-
G protein-coupled receptor 113P02.035-
Gpr125 proteinP02.950-
EGF-like module containing mucin-like hormone receptor-like 1 (Mus musculus) [Ser->Ala replacement]P02.951-
protocadherin Flamingo 2P02.953-
Cirl (Drosophila melanogaster)P02.A01-
lat-1 g.p. (Caenorhabditis elegans)P02.A02-
si:ch211-119b12.8 g.p. (Brachydanio rerio)P02.A03-
si:dkey-30j22.5 g.p. (Brachydanio rerio)P02.A04-
LOC793123 g.p. (Brachydanio rerio)P02.A05-
LOC797830 g.p. (Brachydanio rerio)P02.A06-
LOC799479 g.p. (Brachydanio rerio)P02.A07-
family S63 non-peptidase homologuenon-peptidase homologue-
subfamily P02A unassigned peptidaseunassigned-
Subfamily P2B
Name Peptidase subfamily P2B
Subfamily type peptidase P02.036 - polycystin-1 (Homo sapiens), MEROPS Accession MER0126824 (peptidase unit: 3012-3061)
Active site residues T3049 
Statistics Sequences: 529
Identifiers: 4
Identifiers with PDB entries: 1
Other databases CATH 2.60.40.670
HOMSTRAD PKD
INTERPRO IPR000203
PANTHER PTHR10877
PFAM PF01825
SCOP 49302
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
polycystin-1P02.036Yes
KIAA1879 proteinP02.038-
polycystic kidney disease 1-like 3P02.039-
receptor for egg jelly 3 protein (Strongylocentrotus purpuratus)P02.040-
subfamily P2B non-peptidase homologuenon-peptidase homologue-
subfamily P2B unassigned peptidaseunassigned-