3D66

Crystal structure of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)

3D66 の概要

• エントリーDOI: 10.2210/pdb3d66/pdb
• 関連するPDBエントリー: 3D67 3D68
• 分子名称: Carboxypeptidase B2, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION (3 entities in total)
• 機能のキーワード: alpha/beta hydrolase fold, carboxypeptidase, glycoprotein, metal-binding, metalloprotease, protease, secreted, zymogen, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 148193.15

構造登録者

Brondijk, T.H.C.,Huizinga, E.G. (登録日: 2008-05-19, 公開日: 2008-07-01, 最終更新日: 2024-11-13)

主引用文献

Marx, P.F.,Brondijk, T.H.,Plug, T.,Romijn, R.A.,Hemrika, W.,Meijers, J.C.M.,Huizinga, E.G.
Crystal structures of TAFI elucidate the inactivation mechanism of activated TAFI: a novel mechanism for enzyme autoregulation
Blood, 112:2803-2809, 2008

PubMed Abstract: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-metallocarboxypeptidase that can be proteolytically activated (TAFIa). TAFIa is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. We studied the intrinsic instability of TAFIa by solving crystal structures of TAFI, a TAFI inhibitor (GEMSA) complex and a quadruple TAFI mutant (70-fold more stable active enzyme). The crystal structures show that TAFIa stability is directly related to the dynamics of a 55-residue segment (residues 296-350) that includes residues of the active site wall. Dynamics of this flap are markedly reduced by the inhibitor GEMSA, a known stabilizer of TAFIa, and stabilizing mutations. Our data provide the structural basis for a model of TAFI auto-regulation: in zymogen TAFI the dynamic flap is stabilized by interactions with the activation peptide. Release of the activation peptide increases dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg302. This represents a novel mechanism of enzyme control that enables TAFI to regulate its activity in plasma in the absence of specific inhibitors.

PubMed: 18559974
DOI: 10.1182/blood-2008-03-146001

実験手法

X-RAY DIFFRACTION (3.1 Å)