| Structural highlights
Disease
PROS_HUMAN Defects in PROS1 are the cause of thrombophilia due to protein S deficiency, autosomal dominant (THPH5) [MIM:612336. A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. However, many adults with heterozygous disease may be asymptomatic. Based on the plasma levels of total and free PROS1 antigen as well as the serine protease-activated protein C cofactor activity, three types of PROS1D have been described: type I, characterized by reduced total and free PROS1 antigen levels together with reduced anticoagulant activity; type III, in which only free PROS1 antigen and PROS1 activity levels are reduced; and the rare type II which is characterized by normal concentrations of both total and free PROS1 antigen, but low cofactor activity.[1] [:][2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] Defects in PROS1 are the cause of thrombophilia due to protein S deficiency, autosomal recessive (THPH6) [MIM:614514. A very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage.
Function
PROS_HUMAN Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Vitamin K-dependent protein S is a cofactor of activated protein C, a serine protease that regulates blood coagulation. Deficiency of protein S can cause venous thrombosis. Protein S has four EGF domains in tandem; domains 2-4 bind calcium with high affinity whereas domains 1-2 mediate interaction with activated protein C. We have now solved the solution structure of the EGF3-4 fragment of protein S. The linker between the two domains is similar to what has been observed in other calcium-binding EGF domains where it provides an extended conformation. Interestingly, a disagreement between NOE and RDC data revealed a conformational heterogeneity within EGF3 due to a hinge-like motion around Glu186 in the Cys-Glu-Cys sequence, the only point in the domain where flexibility is allowed. The dominant, bent conformation of EGF3 in the pair has no precedent among calcium-binding EGF domains. It is characterized by a change in the psi angle of Glu186 from 160 degrees +/- 40 degrees , as seen in ten other EGF domains, to approximately 0 degrees +/- 15 degrees . NOESY data suggest that Tyr193, a residue not conserved in other calcium-binding EGF domains (except in the homologue Gas6), induces the unique fold of EGF3. However, SAXS data, obtained on EGF1-4 and EGF2-4, showed a dominant, extended conformation in these fragments. This may be due to a counterproductive domain-domain interaction between EGF2 and EGF4 if EGF3 is in a bent conformation. We speculate that the ability of EGF3 to adopt different conformations may be of functional significance in protein-protein interactions involving protein S.
Solution structure of the Ca2+-Binding EGF3-4 pair from vitamin K-dependent protein S: identification of an unusual fold in EGF3.,Drakenberg T, Ghasriani H, Thulin E, Thamlitz AM, Muranyi A, Annila A, Stenflo J Biochemistry. 2005 Jun 21;44(24):8782-9. PMID:15952784[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gomez E, Poort SR, Bertina RM, Reitsma PH. Identification of eight point mutations in protein S deficiency type I--analysis of 15 pedigrees. Thromb Haemost. 1995 May;73(5):750-5. PMID:7482398
- ↑ Hayashi T, Nishioka J, Shigekiyo T, Saito S, Suzuki K. Protein S Tokushima: abnormal molecule with a substitution of Glu for Lys-155 in the second epidermal growth factor-like domain of protein S. Blood. 1994 Feb 1;83(3):683-90. PMID:8298131
- ↑ Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud M, Dreyfus M, Matheron C, Gaussem P, Abgrall JF, Jude B, Sie P, et al.. Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood. 1995 Jan 1;85(1):130-8. PMID:7803790
- ↑ Formstone CJ, Wacey AI, Berg LP, Rahman S, Bevan D, Rowley M, Voke J, Bernardi F, Legnani C, Simioni P, Girolami A, Tuddenham EG, Kakkar VV, Cooper DN. Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy. Blood. 1995 Oct 1;86(7):2632-41. PMID:7545463
- ↑ Mustafa S, Pabinger I, Mannhalter C. Protein S deficiency type I: identification of point mutations in 9 of 10 families. Blood. 1995 Nov 1;86(9):3444-51. PMID:7579449
- ↑ Li M, Long GL. Identification of two novel point mutations in the human protein S gene associated with familial protein S deficiency and thrombosis. Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1407-15. PMID:8977443
- ↑ Yamazaki T, Katsumi A, Kagami K, Okamoto Y, Sugiura I, Hamaguchi M, Kojima T, Takamatsu J, Saito H. Molecular basis of a hereditary type I protein S deficiency caused by a substitution of Cys for Arg474. Blood. 1996 Jun 1;87(11):4643-50. PMID:8639833
- ↑ Beauchamp NJ, Daly ME, Cooper PC, Makris M, Preston FE, Peake IR. Molecular basis of protein S deficiency in three families also showing independent inheritance of factor V leiden. Blood. 1996 Sep 1;88(5):1700-7. PMID:8781426
- ↑ Simmonds RE, Ireland H, Kunz G, Lane DA. Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Protein S Study Group. Blood. 1996 Dec 1;88(11):4195-204. PMID:8943854
- ↑ Borgel D, Duchemin J, Alhenc-Gelas M, Matheron C, Aiach M, Gandrille S. Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies. J Lab Clin Med. 1996 Aug;128(2):218-27. PMID:8765219
- ↑ Duchemin J, Borg JY, Borgel D, Vasse M, Leveque H, Aiach M, Gandrille S. Five novel mutations of the protein S active gene (PROS 1) in 8 Norman families. Thromb Haemost. 1996 Mar;75(3):437-44. PMID:8701404
- ↑ Bustorff TC, Freire I, Gago T, Crespo F, David D. Identification of three novel mutations in hereditary protein S deficiency. Thromb Haemost. 1997 Jan;77(1):21-5. PMID:9031443
- ↑ Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Aiach M. Protein S deficiency: a database of mutations. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997 Jun;77(6):1201-14. PMID:9241758
- ↑ Espinosa-Parrilla Y, Morell M, Souto JC, Tirado I, Fontcuberta J, Estivill X, Sala N. Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency. Hum Mutat. 1999;14(1):30-9. PMID:10447256 doi:<30::AID-HUMU4>3.0.CO;2-X 10.1002/(SICI)1098-1004(1999)14:1<30::AID-HUMU4>3.0.CO;2-X
- ↑ Hermida J, Faioni EM, Mannucci PM. Poor relationship between phenotypes of protein S deficiency and mutations in the protein S alpha gene. Thromb Haemost. 1999 Dec;82(6):1634-8. PMID:10613647
- ↑ Makris M, Leach M, Beauchamp NJ, Daly ME, Cooper PC, Hampton KK, Bayliss P, Peake IR, Miller GJ, Preston FE. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood. 2000 Mar 15;95(6):1935-41. PMID:10706858
- ↑ Espinosa-Parrilla Y, Morell M, Borrell M, Souto JC, Fontcuberta J, Estivill X, Sala N. Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in the PROS1 gene: identification of seven novel mutations and three novel, apparently neutral, variants. Hum Mutat. 2000;15(5):463-73. PMID:10790208 doi:<463::AID-HUMU8>3.0.CO;2-E 10.1002/(SICI)1098-1004(200005)15:5<463::AID-HUMU8>3.0.CO;2-E
- ↑ Iwaki T, Mastushita T, Kobayashi T, Yamamoto Y, Nomura Y, Kagami K, Nakayama T, Sugiura I, Kojima T, Takamatsu J, Kanayama N, Saito H. DNA sequence analysis of protein S deficiency--identification of four point mutations in twelve Japanese subjects. Semin Thromb Hemost. 2001;27(2):155-60. PMID:11372770 doi:10.1055/s-2001-14075
- ↑ Andersen BD, Bisgaard ML, Lind B, Philips M, Villoutreix B, Thorsen S. Characterization and structural impact of five novel PROS1 mutations in eleven protein S-deficient families. Thromb Haemost. 2001 Dec;86(6):1392-9. PMID:11776305
- ↑ Rezende SM, Lane DA, Mille-Baker B, Samama MM, Conard J, Simmonds RE. Protein S Gla-domain mutations causing impaired Ca(2+)-induced phospholipid binding and severe functional protein S deficiency. Blood. 2002 Oct 15;100(8):2812-9. PMID:12351389 doi:10.1182/blood-2002-03-0909
- ↑ Rezende SM, Lane DA, Zoller B, Mille-Baker B, Laffan M, Dalhback B, Simmonds RE. Genetic and phenotypic variability between families with hereditary protein S deficiency. Thromb Haemost. 2002 Feb;87(2):258-65. PMID:11858485
- ↑ Tsuda H, Urata M, Tsuda T, Wakiyama M, Iida H, Nakahara M, Kinoshita S, Hamasaki N. Four missense mutations identified in the protein S gene of thrombosis patients with protein S deficiency: effects on secretion and anticoagulant activity of protein S. Thromb Res. 2002 Feb 1;105(3):233-9. PMID:11927129
- ↑ Boinot C, Borgel D, Kitzis A, Guicheteau M, Aiach M, Alhenc-Gelas M. Familial thrombophilia is an oligogenetic disease: involvement of the prothrombin G20210A, PROC and PROS gene mutations. Blood Coagul Fibrinolysis. 2003 Feb;14(2):191-6. PMID:12632031 doi:10.1097/01.mbc.0000046180.72384.39
- ↑ Okada H, Takagi A, Murate T, Adachi T, Yamamoto K, Matsushita T, Takamatsu J, Sugita K, Sugimoto M, Yoshioka A, Yamazaki T, Saito H, Kojima T. Identification of protein Salpha gene mutations including four novel mutations in eight unrelated patients with protein S deficiency. Br J Haematol. 2004 Jul;126(2):219-25. PMID:15238143 doi:10.1111/j.1365-2141.2004.05026.x
- ↑ Biguzzi E, Razzari C, Lane DA, Castaman G, Cappellari A, Bucciarelli P, Fontana G, Margaglione M, D'Andrea G, Simmonds RE, Rezende SM, Preston R, Prisco D, Faioni EM. Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study. Hum Mutat. 2005 Mar;25(3):259-69. PMID:15712227 doi:10.1002/humu.20136
- ↑ Drakenberg T, Ghasriani H, Thulin E, Thamlitz AM, Muranyi A, Annila A, Stenflo J. Solution structure of the Ca2+-Binding EGF3-4 pair from vitamin K-dependent protein S: identification of an unusual fold in EGF3. Biochemistry. 2005 Jun 21;44(24):8782-9. PMID:15952784 doi:http://dx.doi.org/10.1021/bi050101f
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