| Structural highlights
Disease
ATS13_HUMAN Defects in ADAMTS13 are the cause of thrombotic thrombocytopenic purpura congenital (TTP) [MIM:274150; also known as Upshaw-Schulman syndrome (USS). A hematologic disease characterized by hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and non-focal neurologic findings, decreased renal function and fever.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Function
ATS13_HUMAN Cleaves the vWF multimers in plasma into smaller forms.
Publication Abstract from PubMed
BACKGROUND: An East Asian-specific P475S polymorphism in the gene encoding ADAMTS-13 causes an approximately 16% reduction in plasma ADAMTS-13 activity. OBJECTIVES: To demonstrate the impact of this dysfunctional polymorphism by characterizing the structure and activity of the P475S mutant protein. METHODS: We determined the crystal structure of the P475S mutant of ADAMTS-13-DTCS (DTCS-P475S, residues 287-685) and compared it with the wild-type structure. We determined the enzymatic parameters of ADAMTS-13-MDTCS (residues 75-685) and MDTCS-P475S, and further examined the effects of denaturants and reaction temperature on their activity. We also examined the cleavage of shear-treated von Willebrand factor (VWF) by MDTCS-P475S. RESULTS: MDTCS-P475S showed a reaction rate similar to that of wild-type MDTCS, but showed two-fold lower affinity for the peptidyl substrate, indicating that the Pro475-containing V-loop (residues 474-481) in the CA domain is a substrate-binding exosite. Structural analysis showed that the conformation of the V-loop was significantly different in DTCS-P475S and the wild type, where no obvious interactions of Ser475 with other residues were observed. This explains the higher susceptibility of the enzymatic activity of MDTCS-P475S to reaction environments such as denaturants and high temperature. MDTCS-P475S can moderately cleave shear-treated VWF. CONCLUSIONS: We have provided structural evidence that the P475S polymorphism in ADAMTS-13 leads to increased local structural instability, resulting in lowered affinity for the substrate without changing the reaction rate. The moderate activity of ADAMTS-13-P475S for shear-treated VWF is sufficient to prevent thrombotic thrombocytopenic purpura (TTP) onset.
Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism.,Akiyama M, Nakayama D, Takeda S, Kokame K, Takagi J, Miyata T J Thromb Haemost. 2013 Jul;11(7):1399-406. doi: 10.1111/jth.12279. PMID:23621748[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001 Oct 4;413(6855):488-94. PMID:11586351 doi:10.1038/35097008
- ↑ Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, Tamai H, Konno M, Kamide K, Kawano Y, Miyata T, Fujimura Y. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11902-7. Epub 2002 Aug 14. PMID:12181489 doi:10.1073/pnas.172277399
- ↑ Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, Drewke E, Hassenpflug W, Haberle J, Kentouche K, Kohne E, Kurnik K, Mueller-Wiefel D, Obser T, Santer R, Sykora KW. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood. 2003 Mar 1;101(5):1845-50. Epub 2002 Oct 17. PMID:12393505 doi:10.1182/blood-2002-08-2399
- ↑ Antoine G, Zimmermann K, Plaimauer B, Grillowitzer M, Studt JD, Lammle B, Scheiflinger F. ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13. Br J Haematol. 2003 Mar;120(5):821-4. PMID:12614216
- ↑ Assink K, Schiphorst R, Allford S, Karpman D, Etzioni A, Brichard B, van de Kar N, Monnens L, van den Heuvel L. Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. Kidney Int. 2003 Jun;63(6):1995-9. PMID:12753286 doi:10.1046/j.1523-1755.63.6s.1.x
- ↑ Pimanda JE, Maekawa A, Wind T, Paxton J, Chesterman CN, Hogg PJ. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Blood. 2004 Jan 15;103(2):627-9. Epub 2003 Sep 25. PMID:14512317 doi:10.1182/blood-2003-04-1346
- ↑ Matsumoto M, Kokame K, Soejima K, Miura M, Hayashi S, Fujii Y, Iwai A, Ito E, Tsuji Y, Takeda-Shitaka M, Iwadate M, Umeyama H, Yagi H, Ishizashi H, Banno F, Nakagaki T, Miyata T, Fujimura Y. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood. 2004 Feb 15;103(4):1305-10. Epub 2003 Oct 16. PMID:14563640 doi:10.1182/blood-2003-06-1796
- ↑ Uchida T, Wada H, Mizutani M, Iwashita M, Ishihara H, Shibano T, Suzuki M, Matsubara Y, Soejima K, Matsumoto M, Fujimura Y, Ikeda Y, Murata M. Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. Blood. 2004 Oct 1;104(7):2081-3. Epub 2004 May 4. PMID:15126318 doi:10.1182/blood-2004-02-0715
- ↑ Veyradier A, Lavergne JM, Ribba AS, Obert B, Loirat C, Meyer D, Girma JP. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J Thromb Haemost. 2004 Mar;2(3):424-9. PMID:15009458
- ↑ Licht C, Stapenhorst L, Simon T, Budde U, Schneppenheim R, Hoppe B. Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). Kidney Int. 2004 Sep;66(3):955-8. PMID:15327386 doi:10.1111/j.1523-1755.2004.00841.x
- ↑ Plaimauer B, Fuhrmann J, Mohr G, Wernhart W, Bruno K, Ferrari S, Konetschny C, Antoine G, Rieger M, Scheiflinger F. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood. 2006 Jan 1;107(1):118-25. Epub 2005 Sep 13. PMID:16160007 doi:2005-06-2482
- ↑ Peyvandi F, Lavoretano S, Palla R, Valsecchi C, Merati G, De Cristofaro R, Rossi E, Mannuccio Mannucci P. Mechanisms of the interaction between two ADAMTS13 gene mutations leading to severe deficiency of enzymatic activity. Hum Mutat. 2006 Apr;27(4):330-6. PMID:16453338 doi:10.1002/humu.20267
- ↑ Tao Z, Anthony K, Peng Y, Choi H, Nolasco L, Rice L, Moake JL, Dong JF. Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. J Thromb Haemost. 2006 Sep;4(9):1931-5. Epub 2006 Jun 22. PMID:16796708 doi:10.1111/j.1538-7836.2006.02098.x
- ↑ Shibagaki Y, Matsumoto M, Kokame K, Ohba S, Miyata T, Fujimura Y, Fujita T. Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw-Schulman syndrome showing predominant episodes of repeated acute renal failure. Nephrol Dial Transplant. 2006 May;21(5):1289-92. Epub 2006 Jan 31. PMID:16449289 doi:gfk072
- ↑ Schneppenheim R, Kremer Hovinga JA, Becker T, Budde U, Karpman D, Brockhaus W, Hrachovinova I, Korczowski B, Oyen F, Rittich S, von Rosen J, Tjonnfjord GE, Pimanda JE, Wienker TF, Lammle B. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006 Jul;96(1):3-6. PMID:16807643 doi:10.1160/TH05-12-0817
- ↑ Donadelli R, Banterla F, Galbusera M, Capoferri C, Bucchioni S, Gastoldi S, Nosari S, Monteferrante G, Ruggeri ZM, Bresin E, Scheiflinger F, Rossi E, Martinez C, Coppo R, Remuzzi G, Noris M. In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura. Thromb Haemost. 2006 Oct;96(4):454-64. PMID:17003922
- ↑ Meyer SC, Jeddi R, Meddeb B, Gouider E, Lammle B, Kremer Hovinga JA. A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13. Ann Hematol. 2008 Aug;87(8):663-6. doi: 10.1007/s00277-008-0496-6. Epub 2008 Apr , 29. PMID:18443791 doi:10.1007/s00277-008-0496-6
- ↑ Fujimura Y, Matsumoto M, Kokame K, Isonishi A, Soejima K, Akiyama N, Tomiyama J, Natori K, Kuranishi Y, Imamura Y, Inoue N, Higasa S, Seike M, Kozuka T, Hara M, Wada H, Murata M, Ikeda Y, Miyata T, George JN. Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients. Br J Haematol. 2009 Mar;144(5):742-54. doi: 10.1111/j.1365-2141.2008.07515.x., Epub 2008 Nov 26. PMID:19055667 doi:10.1111/j.1365-2141.2008.07515.x
- ↑ Palla R, Lavoretano S, Lombardi R, Garagiola I, Karimi M, Afrasiabi A, Ramzi M, De Cristofaro R, Peyvandi F. The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura. Haematologica. 2009 Feb;94(2):289-93. doi: 10.3324/haematol.13524. Epub 2008 Dec , 30. PMID:19116307 doi:10.3324/haematol.13524
- ↑ Lee SH, Park JH, Park SK, Lee EH, Choi JI, Visentin GP, Park TS, Oh SH, Kim SR. A novel homozygous missense ADAMTS13 mutation Y658C in a patient with recurrent thrombotic thrombocytopenic purpura. Ann Clin Lab Sci. 2011 Summer;41(3):273-6. PMID:22075512
- ↑ Akiyama M, Nakayama D, Takeda S, Kokame K, Takagi J, Miyata T. Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. J Thromb Haemost. 2013 Jul;11(7):1399-406. PMID:23621748 doi:10.1111/jth.12279
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