4C2B

Crystal Structure of High-Affinity von Willebrand Factor A1 domain with Disulfide Mutation in Complex with High Affinity GPIb alpha

4C2B の概要

• エントリーDOI: 10.2210/pdb4c2b/pdb
• 関連するPDBエントリー: 4C29 4C2A
• 分子名称: VON WILLEBRAND FACTOR, PLATELET GLYCOPROTEIN IB ALPHA CHAIN, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: blood clotting
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Secreted: P04275; Membrane; Single-pass type I membrane protein: P07359
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 230057.11

構造登録者

Blenner, M.A.,Dong, X.,Springer, T.A. (登録日: 2013-08-16, 公開日: 2014-01-08, 最終更新日: 2024-11-13)

主引用文献

Blenner, M.A.,Dong, X.,Springer, T.A.
Towards the Structural Basis of Regulation of Von Willebrand Factor Binding to Glycoprotein Ib
J.Biol.Chem., 289:5565-, 2014

PubMed Abstract: Activation by elongational flow of von Willebrand factor (VWF) is critical for primary hemostasis. Mutations causing type 2B von Willebrand disease (VWD), platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF A1 domain and platelet glycoprotein Ibα (GPIbα) for one another; however, the structural basis for these observations remains elusive. Directed evolution was used to discover a further gain-of-function mutation in A1 that shifts the long range disulfide bond by one residue. We solved multiple crystal structures of this mutant A1 and A1 containing two VWD mutations complexed with GPIbα containing two PT-VWD mutations. We observed a gained interaction between A1 and the central leucine-rich repeats (LRRs) of GPIbα, previously shown to be important at high shear stress, and verified its importance mutationally. These findings suggest that structural changes, including central GPIbα LRR-A1 contact, contribute to VWF affinity regulation. Among the mutant complexes, variation in contacts and poor complementarity between the GPIbα β-finger and the region of A1 harboring VWD mutations lead us to hypothesize that the structures are on a pathway to, but have not yet reached, a force-induced super high affinity state.

PubMed: 24391089
DOI: 10.1074/JBC.M113.511220

実験手法

X-RAY DIFFRACTION (2.8 Å)