臨床検査55巻4号

2011年04月発行

今月の主題 静脈血栓塞栓症と凝固制御因子プロテインS 総論

凝固制御因子プロテインSの構造と機能

著者： 鈴木宏治¹ 林辰弥²

所属機関： ¹三重大学 ²三重県立看護大学生化学

ページ範囲：P.340 - P.346

プロテインSは，肝臓や血管内皮細胞などで産生されるビタミンK依存性血漿蛋白質で，主として抗凝固セリンプロテアーゼの活性化プロテインC(APC)の阻害因子として機能する．プロテインSは，血漿中ではその約40％が遊離型として，その約60％が補体系制御蛋白質のC4b結合蛋白質(C4BP)との複合体として存在し，遊離型のみがAPCに対するコファクター活性を有する．最近，プロテインSのAPCコファクター以外の機能が明らかになりつつある．

参考文献

1) 岩永貞明：止血・血栓・線溶．(松田道生，鈴木宏治編)，中外医学社，pp103-109，1994

2) 鈴木宏治：血液凝固制御系の異常．図説　分子病態学　第4版(一瀬白帝，鈴木宏治編)，中外医学社，pp262-270，2008

3) Walker FJ:Regulation of activated protein C by protein S:The role of phospholipid in factor Va inactivation. J Biol Chem　256：11128-11131，1981

4) Suzuki K, Nishioka J, Matsuda M, et al:Protein S is essential for the activated protein C-catalyzed inactivation of platelet associated factor Va. J Biochem　96：455-460，1983

5) Walker FJ, Chavin SI, Fay P:Inactivation of factor VIII by activated protein C and protein S. Arch Biochem Biophys　252：322-328，1987

6) Gandrille S, Borgel D, Ireland H, et al: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　77：1201-1214，1997

7) Saller F, Brisset AC, Tchaikovski SN, et al:Generation and phenotypic analysis of protein S-deficient mice. Blood　114：2307-2314，2009

8) Burstyn-Cohen T, Heeb MJ, Lemke G:Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest　119：2942-2953，2009

9) Heeb MJ, Rosing J, Bakker HM, et al:Protein S binds to and inhibits factor Xa. Proc Natl Acad Sci USA　91：2728-2732，1994

10) Heeb MJ, Mesters RM, Tans G, et al:Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem　268：2872-2877，1993

11) Hackeng TM, Sere KM, Tans G, et al:Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA　103：3106-3111，2006

12) Dahlback B:Protein S and C4b-binding protein:components involved in the regulation of the protein C anticoagulant system. Thromb Haemost　66：49-61，1991

13) Rezende SM, Simmonds RE, Lane DA:Coagulation, inflammation, and apoptosis:different roles for protein S and the protein S-C4b binding protein complex. Blood　103：1192-1201，2004

14) Nishioka J, Suzuki K:Inhibition of cofactor activity of protein S by a complex of protein S and C4b-binding protein. Evidence for inactive ternary complex formation between protein S, C4b-binding protein, and activated protein C. J Biol Chem　265：9072-9076，1990

15) Schmidel DK, Tatro AV, Phelps LG, et al:Organization of human protein S genes. Biochemistry　29：7845-7852，1990

16) Ploos van Amstel JK, Reitsma PH, van der Logt PE, et al:Intron-exon organization of the active human protein S gene PSα and its pseudogene PSβ:Duplication and silencing during primate evolution. Biochemistry　29：7853-7860，1990

17) Edenbrandt CM, Lundwall A, Wydro R, et al:Molecular analysis of the gene for vitamin K-dependent protein S and its pseudogene. Cloning and partial gene organization. Biochemistry　29：7861-7868，1990

18) Lundwall A, Dackowski W, Cohen E, et al:Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Proc Natl Acad Sci USA　88：6716-6720，1986

19) Hoskins J, Norman DK, Beckmann RJ, et al:Cloning and characterization of human liver cDNA encoding a protein S precursor. Proc Natl Acad Sci USA　84：349-353，1987

20) Nelson RM, Long GL:Binding of protein S to C4b-binding protein. Mutagenesis of protein S. J Biol Chem　267：8140-8145，1992

21) Hackeng TM, van't Veer C, Meijers JC, et al:Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem　269：21051-21058，1994

22) Chung LP, Bentley DR, Reid KB:Molecular cloning and characterization of the cDNA coding for C4b-binding protein, a regulatory protein of the classical pathway of the human complement system. Biochem J　230：133-141，1985

23) Hillarp A, Dahlback B:Cloning of cDNA coding for the beta chain of human complement component C4b-binding protein:sequence homology with the alpha chain. Proc Natl Acad Sci USA　87：1183-1187，1990

24) Aso T, Okamura S, Matsuguchi T, et al:Genomic organization of the alpha chain of the human C4b-binding protein gene. Biochem Biophys Res Commun　174：222-227，1991

25) Pardo-Manuel F, Rey-Campos J, Hillarp A, et al:Human genes for the alpha and beta chains of complement C4b-binding protein are closely linked in a head-to-tail arrangement. Proc Natl Acad Sci USA　87：4529-4532，1990

26) Hillarp A, Pardo-Manuel F, Ruiz RR, et al:The human C4b-binding protein beta-chain gene. J Biol Chem　268：15017-15023，1993

27) Hayashi T, Nishioka J, Suzuki K:Molecular mechanism of the dysfunction of protein S (Tokushima) (Lys155--＞Glu) for the regulation of the blood coagulation system. Biochim Biophys Acta　1271：159-167，1995

28) Mille-Baker B, Rezende SM, Simmonds RE, et al:Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity. Blood　101：1416-1418，2003

29) Hillarp A, Dahlback B:Novel subunit in C4b-binding protein required for protein S binding. J Biol Chem　263：12759-12764，1988

30) Ndonwi M, Tuley EA, Broze GJ Jr:The Kunitz-3 domain of TFPI-alpha is required for protein S-dependent enhancement of factor Xa inhibition. Blood　116：1344-1351，2010

31) Pabinger I, Lechner K:Acquired protein C and protein S deficiency. In:Protein C and Related Proteins" (Bertina RC ed), Churchill Livingstone, Edinburgh，p213，1988

32) Madden RM, Gill JC, Marlar RA:Protein C and protein S levels in two patients with acquired purpura fulminans. Br J Haematol　75：112-117，1990

33) Keeling DM, Campbell SJ, Mackie IJ, et al:Total and free protein S in systemic lupus erythematosus. Thromb Res　60：237-240，1990

34) Hayashi T, Kishiwada M, Fujii K, et al:Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFκB activation. Involvement of membrane-bound CD14 and Toll-like receptor-4. J Thromb Haemost　4：1763-1773，2006

35) Kishiwada M, Hayashi T, Yuasa H, et al:Regulatory mechanisms of C4b-binding protein (C4BP)α and β expression in rat hepatocytes by lipopolysaccharide and interleukin-6-specific increase of C4BPβ expression influences the plasma level of protein S-C4BP complex and anticoagulant activity of protein S. J Thromb Haemost　6：1858-1867，2008

36) Quehenberger P, Loner U, Kapiotis S, et al:Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost　76：729-734，1996

37) Suzuki A, Sanda N, Miyawaki Y, et al:Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex. J Biol Chem　285：13444-13453，2010

38) Schwarz HP, Muntean W, Watzke H, et al:Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates. Blood　71：562-565，1988

39) Hesselvik JF, Malm J, Dahlback B, et al:Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost　65：126-129，1991

40) Tsakiris DA, Settas L, Makris PE, et al:Lupus anticoagulant-antiphospholipid antibodies and thrombophilia. Relation to protein C--protein S―thrombomodulin. J Rheumatol　17：785-789，1990

41) Liu D, Guo H, Griffin JH, et al:Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation　107：1791-1796，2003

42) Zhong Z, Wang Y, Guo H, et al:Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region. J Neurosci　30：15521-15534，2010

43) Fernandez JA, Heeb MJ, Xu X, et al:Species-specific anticoagulant and mitogenic activities of murine protein S. Haematologica　94：1721-1731，2009

44) Anderson HA, Maylock CA, Williams JA, et al:Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol　4：87-91，2003

45) Uehara H, Shacter E:Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol　180：2522-2530，2008

46) Takagi T, Taguchi O, Aoki S, et al:Direct effects of protein S in ameliorating acute lung injury. J Thromb Haemost　7：2053-2063，2009