Center for Biochemistry, Medical Faculty, Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany.
Centre for Biological Sciences, B85 Life Sciences Building M55, University of Southampton, Southampton SO17 1BJ, UK.
Structure. 2014 Feb 4;22(2):199-208. doi: 10.1016/j.str.2013.06.028. Epub 2013 Dec 12.
Von Willebrand factor A (VWA) domains are versatile protein interaction domains with N and C termini in close proximity placing spatial constraints on overall protein structure. The 1.2 Å crystal structures of a collagen VI VWA domain and a disease-causing point mutant show C-terminal extensions that place the N and C termini at opposite ends. This allows a "beads-on-a-string" arrangement of multiple VWA domains as observed for ten N-terminal domains of the collagen VI α3 chain. The extension is linked to the core domain by a salt bridge and two hydrophobic patches. Comparison of the wild-type and a muscular dystrophy-associated mutant structure identifies a potential perturbation of a protein interaction interface and indeed, the secretion of mutant collagen VI tetramers is affected. Homology modeling is used to locate a number of disease-associated mutations and analyze their structural impact, which will allow mechanistic analysis of collagen-VI-associated muscular dystrophy phenotypes.
血管性血友病因子 A（VWA）结构域是多功能的蛋白质相互作用结构域，其 N 末端和 C 末端非常接近，从而对整体蛋白质结构产生空间限制。胶原 VI VWA 结构域和一种致病点突变体的 1.2Å 晶体结构显示出 C 末端延伸，从而使 N 末端和 C 末端位于相对的两端。这允许如观察到的胶原 VI α3 链的十个 N 末端结构域那样，形成多个 VWA 结构域的“串珠”排列。该延伸通过盐桥和两个疏水区与核心结构域相连。对野生型和与肌肉萎缩症相关的突变体结构的比较确定了蛋白质相互作用界面的潜在干扰，实际上，突变型胶原 VI 四聚体的分泌受到影响。同源建模用于定位许多与疾病相关的突变，并分析其结构影响，这将允许对与胶原 VI 相关的肌肉萎缩症表型进行机制分析。
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