Protein S

Protein S (also known as S-Protein)

is a vitamin K-dependent plasma
PROS1
glycoprotein synthesized in the liver.
In the circulation, Protein S exists in
two forms: a free form and a
complex form bound to complement
protein C4b-binding protein (C4BP).
In humans, protein S is encoded by
the PROS1 gene.[5][6]
Available structures
PDB Ortholog search: PDBe (https://www.ebi.ac.uk/pdbe/search
Contents Results.html?display=both&term=Q08761%20or%20P0722
5) RCSB (http://www.rcsb.org/pdb/search/smartSubquery.d
History
o?smartSearchSubtype=UpAccessionIdQuery&accessionId
Structure
List=Q08761,P07225)
Function
List of PDB id codes
Pathology
Interactions 1Z6C (https://www.rcsb.org/structure/1Z6C)
See also
References Identifiers

Further reading Aliases PROS1 (https://www.genenames.org/data/gene-symbol-r

eport/#!/hgnc_id/9456), PROS, PS21, PS22, PS23, PS24,
PS25, PSA, THPH5, THPH6, protein S (alpha), protein S
History External OMIM: 176880 (https://omim.org/entry/176880) MGI:
IDs 1095733 (http://www.informatics.jax.org/marker/MGI:109
Protein S is named for Seattle, 5733) HomoloGene: 264 (https://www.ncbi.nlm.nih.gov/e
Washington, where it was originally ntrez/query.fcgi?cmd=Retrieve&db=homologene&dopt=H
discovered and purified[7] by Earl omoloGene&list_uids=264) GeneCards: PROS1 (https://
Davie's group in 1977.[8] www.genecards.org/cgi-bin/carddisp.pl?gene=PROS1)

Gene location (Human)

Structure
Protein S is partly homologous to
other vitamin K-dependent plasma
coagulation proteins, such as protein
C and factors VII, IX, and X. Similar
to them, it has a Gla domain and
several EGF-like domains (four Chr. Chromosome 3 (human)[1]
rather than two), but no serine
protease domain. Instead, there is a
large C-terminus domain that is
homologous to plasma steroid
Band 3q11.1 Start 93,873,051 bp[1]
hormone-binding proteins such as
sex hormone-binding globulin and End 93,980,003 bp[1]
corticosteroid-binding globulin. It
may play a role in the protein Gene location (Mouse)
functions as either a cofactor for
activated protein C (APC) or in
binding C4BP.[9][10]

Additionally, protein S has a peptide

between the Gla domain and the
EGF-like domain, that is cleaved by Chr. Chromosome 16 (mouse)[2]
thrombin. The Gla and EGF-like
domains stay connected after the
cleavage by a disulfide bond.
However, protein S loses its function
as an APC cofactor following either Band 16|16 C1.3 Start 62,854,307 bp[2]
this cleavage or binding C4BP.[11] End 62,929,346 bp[2]

RNA expression pattern

Function
The best characterized function of
Protein S is its role in the anti
coagulation pathway, where it
functions as a cofactor to Protein C
in the inactivation of Factors Va and
VIIIa. Only the free form has
cofactor activity.[12]

Protein S binds to negatively charged More reference expression data (http://biogps.org/gene/5627/)

phospholipids via the carboxylated
Gla domain. This property allows Gene ontology
Protein S to facilitate the removal of Molecular • calcium ion binding (http://amigo.geneontology.org/a
cells that are undergoing apoptosis, a function migo/term/GO:0005509)
form of structured cell death used by
• endopeptidase inhibitor activity (http://amigo.geneon
the body to remove unwanted or
tology.org/amigo/term/GO:0004866)
damaged cells. In healthy cells, an
ATP (adenosine triphosphate)- Cellular • blood microparticle (http://amigo.geneontology.org/a
dependent enzyme removes component migo/term/GO:0072562)
negatively charged phospholipids • endoplasmic reticulum membrane (http://amigo.gen
such as phosphatidyl serine from the eontology.org/amigo/term/GO:0005789)
outer leaflet of the cell membrane.
• Golgi membrane (http://amigo.geneontology.org/ami
An apoptotic cell (that is, one
go/term/GO:0000139)
undergoing apoptosis) no longer
actively manages the distribution of • cell membrane (http://amigo.geneontology.org/amig
phospholipids in its outer membrane o/term/GO:0005886)
and hence begins to display • extracellular region (http://amigo.geneontology.org/a
negatively charged phospholipids on migo/term/GO:0005576)
its exterior surface. These negatively • Golgi lumen (http://amigo.geneontology.org/amigo/te
charged phospholipids are rm/GO:0005796)
recognized by phagocytes such as
• extracellular exosome (http://amigo.geneontology.or
macrophages. Protein S binds to the
negatively charged phospholipids g/amigo/term/GO:0070062)
and functions as a bridge between • platelet alpha granule lumen (http://amigo.geneontol
the apoptotic cell and the phagocyte. ogy.org/amigo/term/GO:0031093)
This bridging expedites phagocytosis • extracellular (http://amigo.geneontology.org/amigo/te
and allows the cell to be removed rm/GO:0005615)
without giving rise to inflammation
Biological • hemostasis (http://amigo.geneontology.org/amigo/ter
or other signs of tissue damage.
process m/GO:0007599)
Protein S also binds to the nascent • fibrinolysis (http://amigo.geneontology.org/amigo/ter
complement complex C5,6,7 and m/GO:0042730)
prevents this complex from inserting • platelet degranulation (http://amigo.geneontology.or
into a membrane. This function
g/amigo/term/GO:0002576)
prevents the inappropriate activation
of the complement system, which • blood coagulation (http://amigo.geneontology.org/am
would cause uncontrolled systemic igo/term/GO:0007596)
inflammation. In fact, Protein S was • ER to Golgi vesicle-mediated transport (http://amigo.
first discovered in 1977 in this role geneontology.org/amigo/term/GO:0006888)
and it is named after the membrane • signal peptide processing (http://amigo.geneontolog
site that it occupies in the y.org/amigo/term/GO:0006465)
complex.[13] • peptidyl-glutamic acid carboxylation (http://amigo.ge
neontology.org/amigo/term/GO:0017187)
Pathology • regulation of complement activation (http://amigo.ge
neontology.org/amigo/term/GO:0030449)
Mutations in the PROS1 gene can • leukocyte migration (http://amigo.geneontology.org/a
lead to Protein S deficiency which is migo/term/GO:0050900)
a rare blood disorder which can lead • negative regulation of endopeptidase activity (http://
to an increased risk of
[14][15] amigo.geneontology.org/amigo/term/GO:0010951)
thrombosis.
• negative regulation of blood coagulation (http://amig
o.geneontology.org/amigo/term/GO:0030195)
Interactions Sources:Amigo (http://amigo.geneontology.org/) / QuickGO (https://
www.ebi.ac.uk/QuickGO/)
Protein S has been shown to interact
with Factor V.[16][17] Orthologs
Species Human Mouse
See also Entrez
5627 (https://www.ncb 19128 (https://www.ncbi.
Hemostasis
i.nlm.nih.gov/entrez/qu nlm.nih.gov/entrez/query.f
ery.fcgi?db=gene&cm cgi?db=gene&cmd=retrie
References d=retrieve&dopt=defa ve&dopt=default&list_uid
ult&list_uids=5627&rn s=19128&rn=1)
1. GRCh38: Ensembl release =1)
89: ENSG00000184500 (htt
p://May2017.archive.ensemb
Ensembl
l.org/Homo_sapiens/Gene/Su
mmary?db=core;g=ENSG000 ENSG00000184500 ENSMUSG00000022912
00184500) - Ensembl, May (http://www.ensembl.o (http://www.ensembl.org/
2017 rg/Homo_sapiens/gen Mus_musculus/genevie
eview?gene=ENSG00 w?gene=ENSMUSG000
000184500;db=core) 00022912;db=core)

UniProt
2. GRCm38: Ensembl release P07225 (https://www.u Q08761 (https://www.uni
89: ENSMUSG00000022912 niprot.org/uniprot/P07 prot.org/uniprot/Q08761)
(http://May2017.archive.ense 225)
mbl.org/Mus_musculus/Gene/
Summary?db=core;g=ENSM RefSeq
USG00000022912) -
Ensembl, May 2017 (mRNA) NM_000313 (https://w NM_011173 (https://ww
3. "Human PubMed Reference:" ww.ncbi.nlm.nih.gov/e w.ncbi.nlm.nih.gov/entre
(https://www.ncbi.nlm.nih.gov/ ntrez/viewer.fcgi?val= z/viewer.fcgi?val=NM_01
sites/entrez?db=gene&cmd= NM_000313) 1173)
Link&LinkName=gene_pubm NM_001314077 (http
ed&from_uid=5627). National s://www.ncbi.nlm.nih.g
Center for Biotechnology ov/entrez/viewer.fcgi?
Information, U.S. National val=NM_001314077)
Library of Medicine.
4. "Mouse PubMed Reference:" RefSeq
(https://www.ncbi.nlm.nih.gov/ (protein) NP_000304 (https://w NP_035303 (https://www.
sites/entrez?db=gene&cmd= ww.ncbi.nlm.nih.gov/e ncbi.nlm.nih.gov/entrez/vi
Link&LinkName=gene_pubm ntrez/viewer.fcgi?val= ewer.fcgi?val=NP_03530
ed&from_uid=19128).
NP_000304) 3)
National Center for
NP_001301006 (http
Biotechnology Information,
U.S. National Library of s://www.ncbi.nlm.nih.g
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val=NP_001301006)
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Further reading
Dahlbäck B (1991). "Protein S and C4b- Rezende SM, Simmonds RE, Lane DA
binding protein: components involved in the (2004). "Coagulation, inflammation, and
regulation of the protein C anticoagulant apoptosis: different roles for protein S and
system". Thromb. Haemost. 66 (1): 49–61. the protein S-C4b binding protein complex"
doi:10.1055/s-0038-1646373 (https://doi.org/ (https://semanticscholar.org/paper/3fb3444b
10.1055%2Fs-0038-1646373). 7c56c94a75b111c60b12e962519d944a).
PMID 1833851 (https://pubmed.ncbi.nlm.nih. Blood. 103 (4): 1192–201.
gov/1833851). doi:10.1182/blood-2003-05-1551 (https://doi.
Witt, I (2002). "Molekularbiologische org/10.1182%2Fblood-2003-05-1551).
Grundlagen und Diagnostik der hereditären PMID 12907438 (https://pubmed.ncbi.nlm.ni
Defekte von Antithrombin III, Protein C und h.gov/12907438).
Protein S" (https://web.archive.org/web/2012 Dahlbäck B (2007). "The tale of protein S
0327063214/http://www.schattauer.de/en/ma and C4b-binding protein, a story of
gazine/subject-areas/journals-a-z/haemosta affection". Thromb. Haemost. 98 (1): 90–6.
seologie/contents/archive/issue/515/manusc doi:10.1160/th07-04-0269 (https://doi.org/10.
ript/1703.html) [Molecular biological basis 1160%2Fth07-04-0269). PMID 17597997 (h
and diagnosis of hereditary defect of ttps://pubmed.ncbi.nlm.nih.gov/17597997).
antithrombin III, protein c and protein S]. García de Frutos P, Fuentes-Prior P, Hurtado
Hamostaseologie (in German). 22 (2): 14– B, Sala N (2007). "Molecular basis of protein
24. doi:10.1267/Hamo02020057 (https://doi. S deficiency". Thromb. Haemost. 98 (3):
org/10.1267%2FHamo02020057) (inactive 543–56. doi:10.1160/th07-03-0199 (https://d
2020-01-22). PMID 12193972 (https://pubm oi.org/10.1160%2Fth07-03-0199).
ed.ncbi.nlm.nih.gov/12193972). Archived PMID 17849042 (https://pubmed.ncbi.nlm.ni
from the original (http://www.schattauer.de/e h.gov/17849042).
n/magazine/subject-areas/journals-a-z/hae
Maillard C, Berruyer M, Serre CM, et al.
mostaseologie/contents/archive/issue/515/m
(1992). "Protein-S, a vitamin K-dependent
anuscript/1703.html) on 2012-03-27. protein, is a bone matrix component
Retrieved 2011-08-19.
synthesized and secreted by osteoblasts".
Endocrinology. 130 (3): 1599–604.
doi:10.1210/en.130.3.1599 (https://doi.org/1
0.1210%2Fen.130.3.1599). PMID 1531628
(https://pubmed.ncbi.nlm.nih.gov/1531628).
Griffin JH, Gruber A, Fernández JA (1992). Ohlin AK, Landes G, Bourdon P, et al.
"Reevaluation of total, free, and bound (1989). "Beta-hydroxyaspartic acid in the
protein S and C4b-binding protein levels in first epidermal growth factor-like domain of
plasma anticoagulated with citrate or protein C. Its role in Ca2+ binding and
hirudin". Blood. 79 (12): 3203–11. biological activity". J. Biol. Chem. 263 (35):
doi:10.1182/blood.V79.12.3203.bloodjourna 19240–8. PMID 2461936 (https://pubmed.nc
l79123203 (https://doi.org/10.1182%2Fbloo bi.nlm.nih.gov/2461936).
d.V79.12.3203.bloodjournal79123203). Schwarz HP, Heeb MJ, Lottenberg R, et al.
PMID 1534488 (https://pubmed.ncbi.nlm.nih. (1989). "Familial protein S deficiency with a
gov/1534488). variant protein S molecule in plasma and
Guglielmone HA, Vides MA (1992). "A novel platelets". Blood. 74 (1): 213–21.
functional assay of protein C in human doi:10.1182/blood.V74.1.213.213 (https://do
plasma and its comparison with amidolytic i.org/10.1182%2Fblood.V74.1.213.213).
and anticoagulant assays". Thromb. PMID 2526663 (https://pubmed.ncbi.nlm.nih.
Haemost. 67 (1): 46–9. doi:10.1055/s-0038- gov/2526663).
1648377 (https://doi.org/10.1055%2Fs-0038 Ploos van Amstel HK, van der Zanden AL,
-1648377). PMID 1615482 (https://pubmed.n Reitsma PH, Bertina RM (1987). "Human
cbi.nlm.nih.gov/1615482). protein S cDNA encodes Phe-16 and Tyr
Bertina RM, Ploos van Amstel HK, van 222 in consensus sequences for the post-
Wijngaarden A, et al. (1990). "Heerlen translational processing". FEBS Lett. 222
polymorphism of protein S, an immunologic (1): 186–90. doi:10.1016/0014-
polymorphism due to dimorphism of residue 5793(87)80217-X (https://doi.org/10.1016%2
460". Blood. 76 (3): 538–48. F0014-5793%2887%2980217-X).
doi:10.1182/blood.V76.3.538.538 (https://do PMID 2820795 (https://pubmed.ncbi.nlm.nih.
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PMID 2143091 (https://pubmed.ncbi.nlm.nih. Dahlbäck B, Lundwall A, Stenflo J (1986).
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Schmidel DK, Tatro AV, Phelps LG, et al. dependent protein S" (https://www.ncbi.nlm.
(1991). "Organization of the human protein nih.gov/pmc/articles/PMC323699). Proc.
S genes". Biochemistry. 29 (34): 7845–52. Natl. Acad. Sci. U.S.A. 83 (12): 4199–203.
doi:10.1021/bi00486a010 (https://doi.org/10. Bibcode:1986PNAS...83.4199D (https://ui.a
1021%2Fbi00486a010). PMID 2148110 (htt dsabs.harvard.edu/abs/1986PNAS...83.419
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