6qig

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Metalloproteinase

Structural highlights

6qig is a 3 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.8Å
Ligands:BMA, CA, CL, FUC, GOL, MAN, NAG, PEG, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity. Thereafter, binding of the ADAMTS13 disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 metalloprotease to spacer domains reveals that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. Our data demonstrate that VWF functions as both the activating cofactor and substrate for ADAMTS13.

Crystal structure and substrate-induced activation of ADAMTS13.,Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, Vanhoorelbeke K, Emsley J, Crawley JTB Nat Commun. 2019 Aug 22;10(1):3781. doi: 10.1038/s41467-019-11474-5. PMID:31439947[21]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management.
Sukumar et al. (2021)
10 more
19 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, Vanhoorelbeke K, Emsley J, Crawley JTB. Crystal structure and substrate-induced activation of ADAMTS13. Nat Commun. 2019 Aug 22;10(1):3781. PMID:31439947 doi:10.1038/s41467-019-11474-5

Contents


PDB ID 6qig

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