3vn4: Difference between revisions

<table><tr><td colspan='2'>[[3vn4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VN4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VN4 FirstGlance]. <br>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>

[https://www.uniprot.org/uniprot/ATS13_HUMAN ATS13_HUMAN] Defects in ADAMTS13 are the cause of thrombotic thrombocytopenic purpura congenital (TTP) [MIM:[https://omim.org/entry/274150 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.<ref>PMID:11586351</ref> <ref>PMID:12181489</ref> <ref>PMID:12393505</ref> <ref>PMID:12614216</ref> <ref>PMID:12753286</ref> <ref>PMID:14512317</ref> <ref>PMID:14563640</ref> <ref>PMID:15126318</ref> <ref>PMID:15009458</ref> <ref>PMID:15327386</ref> <ref>PMID:16160007</ref> <ref>PMID:16453338</ref> <ref>PMID:16796708</ref> <ref>PMID:16449289</ref> <ref>PMID:16807643</ref> <ref>PMID:17003922</ref> <ref>PMID:18443791</ref> <ref>PMID:19055667</ref> <ref>PMID:19116307</ref> <ref>PMID:22075512</ref>  

[https://www.uniprot.org/uniprot/ATS13_HUMAN ATS13_HUMAN] Cleaves the vWF multimers in plasma into smaller forms.

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<ref>PMID:23621748</ref>

[[Category: Homo sapiens]]

[[Category: Akiyama M]]

[[Category: Kokame K]]

[[Category: Miyata T]]

[[Category: Nakayama D]]

[[Category: Takagi J]]

[[Category: Takeda S]]