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0PCSK9_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
NamePCSK9
DescriptionProprotein convertase subtilisin/kexin type 9 precursor (ec 3.4.21.-) (proprotein convertase pc9) (subtilisin/kexin-like protease pc9) (neural apoptosis-regulated convertase 1) (narc-1).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0004289 subtilase activity (NAS)
Domain Architecture (Details)
InterPro domains unassigned to SynO:
Proteolytic enzymes that exploit serine in their catalytic activity areubiquitous.eing found in viruses.acteria and eukaryotes . Theyinclude a wide range of peptidase activity.ncluding exopeptidase.ndopeptidase.ligopeptidase and omega-peptidase activity. Over 20 families(denoted S1 - S27) of serine protease have been identified.hese beinggrouped into 6 clans (SA.B.C.E.F and SG) on the basis of structuralsimilarity and other functional evidence . Structures are known for fourof the clans (SA.B.C and SE): these appear to be totally unrelated.uggesting at least four evolutionary origins of serine peptidases andpossibly many more .Notwithstanding their different evolutionary origins.here are similaritiesin the reaction mechanisms of several peptidases. Chymotrypsin.ubtilisinand carboxypeptidase C clans have a catalytic triad of serine.spartate andhistidine in common: serine acts as a nucleophile.spartate as anelectrophile.nd histidine as a base . The geometric orientations ofthe catalytic residues are similar between families.espite differentprotein folds . The linear arrangements of the catalytic residuescommonly reflect clan relationships. For example the catalytic triad inthe chymotrypsin clan (SA) is ordered HDS.ut is ordered DHS in thesubtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .Peptidases are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry. Families are grouped by their catalytic type.he first character representing the catalytic type: A.spartic; C.ysteine; G.lutamic acid; M.etallo; S.erine; T.hreonine; and U.nknown. A clan that contains families of more than one type is described as being of type P. The serine.hreonine and cysteine peptidases utilise the catalytic part of an amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic.lutamic and metallopeptidases.he nucleophile is an activated water molecule. This group of serine peptidases belong to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin) both of which are members of clan SB.The subtilisin family is the second largest serine protease family characterised to date. Over 200 subtilises are presently known.ore than 170 of which with their complete amino acid sequence . It is widespread.eing found in eubacteria.rchaebacteria.ukaryotes and viruses . The vast majority of the family are endopeptidases.lthough there is an exopeptidase.ripeptidyl peptidase . Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins.lthough the residues occur in a different order (HDS inchymotrypsin and DHS in subtilisin).ut the structures show no othersimilarity . Some subtilisins are mosaic proteins.nd otherscontain N- and C-terminal extensions that show no sequence similarity toany other known protein . Based on sequence homology. subdivision into six families has been proposed . The proprotein-processing endopeptidases kexin.urin and related enzymesform a distinct subfamily known as the kexin subfamily (S8B). These preferentiallycleave C-terminally to paired basic amino acids. Members of this subfamilycan be identified by subtly different motifs around the active site .Members of the kexin family.long with endopeptidases R. and K from theyeast Tritirachium and cuticle-degrading peptidase from Metarhizium.equirethiol activation. This can be attributed to the presence of Cys-173 near tothe active histidine .Only 1 viral member of the subtilisin family is known. 56-kDa protease from herpes virus 1.hich infects the channel catfish . Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however.hey are considerably larger.ith the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad.er-Glu-Asp.s well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101.s well as for kumamolisin from a thermophilic bacterium.acillus novo sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease .
  IPR000209:Peptidase S8 and S53, subtilisin, kexin, sedolisin
Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors.espectively. In many cases they are synthesised as part of a larger precursor protein.ither as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Proteinase propeptide inhibitors (sometimes refered to as activation peptides) are responsible for the modulation of folding and activity of the pro-enzyme or zymogen. The pro-segment docks into the enzyme moiety shielding the substrate binding site.hereby promoting inhibition of the enzyme. Several such propeptides share a similar topology .espite often low sequence identities . The propeptide region has an open-sandwich antiparallel-alpha/antiparallel-beta fold.ith two alpha-helices and four beta-strands with a (beta/alpha/beta)x2 topology.This group of sequences contain the propeptide domain at the N terminus of peptidases belonging to MEROPS family S8A.ubtilisins. A number of the members of this group of sequences belong to MEROPS inhibitor family I9.lan I-. The propeptide is removed by proteolytic cleavage; removal activating the enzyme.
  IPR010259:Proteinase inhibitor I9, subtilisin propeptide
Peptide proteinase inhibitors can be found as single domain proteins or as single or multiple domains within proteins; these are referred to as either simple or compound inhibitors.espectively. In many cases they are synthesised as part of a larger precursor protein.ither as a prepropeptide or as an N-terminal domain associated with an inactive peptidase or zymogen. Removal of the N-terminal inhibitor domain either by interaction with a second peptidase or by autocatalytic cleavage activates the zymogen. Proteinase propeptide inhibitors (sometimes refered to as activation peptides) are responsible for the modulation of folding and activity of the pro-enzyme or zymogen. The pro-segment docks into the enzyme moiety shielding the substrate binding site.hereby promoting inhibition of the enzyme. Several such propeptides share a similar topology .espite often low sequence identities . The propeptide region has an open-sandwich antiparallel-alpha/antiparallel-beta fold.ith two alpha-helices and four beta-strands with a (beta/alpha/beta)x2 topology.This propeptide inhibitor domain occurs widely across all forms of life.nd is found associated with the N-terminal region of a number of MEROPS peptidase families: Metallopeptidase family M14A (carboxypeptidases). These include carboxypeptidase A1.2 .3.4.5.6..nsect gut carboxypeptidase and B . Serine peptidase family S8A (subtilisin family). Members of this group belong to MEROPS inhibitor family I9.lan I-.Serine peptidase family S8B (kexin family). The calcium-dependant serine peptidases belonging to MEROPS family S8B include the Kex2/subtilisin-like proprotein convertase (PC) family.hich have been identified in all eukaryotes.hese include furin.C1/3.nd PC2. The convertases are synthesised as an “inactive precursor proteins or zymogens. Following the N-terminal signal peptide is the prodomain.onsisting of between 80 to 115 residues; it is an integral part ofthe zymogen and acts as a steric chaperone to aid proper folding of the zymogen. An autocatalytic cleavage at the second dibasic site.-X-K-R.iberates the prodomain.ut which remains attached and acts to inhibit any further endopeptidase activity by binding to the catalytic domain. Inhibition is released when the maturing convertase is transported to the trans-Golgi network (TGN) where a decrease in pH causes a second autoproteolytic cleavage to occur at the first dibasic site within the prodomain fragment . The SSF signature in this entry is currently under review. Please be aware that some of the protein hits may be false positives.
  IPR009020:Proteinase inhibitor, propeptide
IPR000209:Peptidase_S8 
Evalue:-31.3098030090332 
Location:180-407IPR010259:Subtilisin_N 
Evalue:-12.6989698410034 
Location:76-152IPR000209:SUBTILASE_ASP 
Evalue:0 
Location:0-0
SequencesProtein: PCSK9_HUMAN (692 aa)
mRNA: NM_174936
Local Annotation
Synapse Ontology
Microglias, one kind of glias in CNS, are responsible for removing most of the waste and cellular debris from the CNS
sdb:0267 removing metabolic mass  (Evidence:keywords)
Calcium release from RyR (Ryanodine Receptor) in the SR (Sarcoplasmic Reticulum) is activated by the calcium induced-calcium-release
sdb:0325 RyR-CICR  (Evidence:keywords)
KO assignmentK01362
  Level 3 annotation:
    
  Level 2 annotation:
    Other amino acid metabolism
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 167 residues, 55277807-55278305Exon2: 66 residues, 55282103-55282295Exon3: 43 residues, 55284783-55284907Exon4: 46 residues, 55290538-55290672Exon5: 49 residues, 55290910-55291052Exon6: 67 residues, 55294253-55294450Exon7: 63 residues, 55295591-55295775Exon8: 60 residues, 55296296-55296470Exon9: 51 residues, 55296759-55296908Exon10: 61 residues, 55297746-55297924Exon11: 62 residues, 55299635-55299817Exon12: 496 residues, 55301629-55303111Exon13: 2 residues, -Jump to PCSK9_HUMAN  
Tune and view alternative isoforms
Loci Cluster (Details)Loci: 3805 55087887-55125493 ~-38K 1573(DHCR24)(-)Loci: 2521 55277807-55303111 ~-25K 1577(PCSK9)(+)Loci: 2520 54786488-54873005 ~-87K 1560(ACOT11)(+)Link out to UCSC