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Paired Basic Amino acid residue-Cleaving Enzyme-4 (PACE4, proprotein convertase subtilisin/kexin type 6, PCSK6, subtilisin-like proprotein convertase 4, SPC4)
Function:
- endoprotease activity within the constitutive secretory pathway, with unique restricted distribution in both neuroendocrine & non-neuroendocrine tissues
- capable of cleavage at the RX(K/R)R consensus motif
- release of mature proteins from their proproteins by cleavage of Arg-Xaa-Yaa-Arg-|-Zaa bonds, where Xaa can be any amino acid & Yaa is Arg or Lys
Cofactor: Ca+2 (putative)
Structure:
- propeptide domain acts as an intramolecular chaperone assisting folding of zymogen within the endoplasmic reticulum
- isoform PACE4D lacks the propeptide domain belongs to the peptidase S8 family
- PACE4A-I precursor protein seems to exist in the endoplasmic reticulum as both a monomer & a dimer
- mature PACE4A-I exists only as a monomer, suggesting that propeptide cleavage affects its tertiary or quaternary structure
- contains 1 homo B/P domain
- contains 1 PLAC domain
Compartment:
- isoform PACE4A-I, PACE4A-II, PACE4B: secreted
- isoform PACE4C, PACE4CS: endoplasmic reticulum not secreted, remains probably in zymogen form in endoplasmic reticulum
- isoform PACE4E-I, PACE4E-II: intracytoplasmic membrane retained intracellularly probably through a hydrophobic cluster in their C-terminus
Alternative splicing: named isoforms=8
PACE4B, PACE4C, PACE4CS, PACE4D probably enzymatically inactive
Expression:
- each PACE4 isoform exhibits a unique restricted distribution
- PACE4A-I is expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver
- PACE4A-II is at least expressed in placenta
- PACE4B was only found in the embryonic kidney cell line from which it was isolated
- PACE4C & PACE4D are expressed in placenta
- PACE4E-I is expressed in cerebellum, placenta & pituitary
- PACE4E-II is at least present in cerebellum
General
glycoprotein
subtilase (serine protease subtilisin family, subtilisin/kexin-like protease)
Properties
SIZE: entity length = 969 aa
MW = 106 kD
COMPARTMENT: cytoplasm
endoplasmic reticulum
MOTIF: signal sequence {1-63}
proteolytic site {149-150}
active site
SITE: 150-454
MOTIF: aspartate residue {D205}
histidine residue {H246}
N-glycosylation site {N259}
serine residue {S420}
Homo B/P {496-634}
MOTIF: Cell attachment site {553-555}
CRM (Cys-rich motif) {695-930}
MOTIF: N-glycosylation site {N914}
PLAC {931-969}
MOTIF: N-glycosylation site {N932}
Database Correlations
OMIM 167405
UniProt P29122
PFAM correlations
Kegg hsa:5046
References
- UniProt :accession P29122
- PROSITE :acccesion PS00136