Antithrombin Mutation Database: 2nd (1997) Update

Abstract

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The Conformational Activation of Antithrombin

“…2 Iterative rounds of rebuilding and refinement were conducted using the programs O (24) and Refmac (25) using the bulk solvent correction of CNS (35). Statistics of the final models are described in the Table I.…”

“…The tight regulation of antithrombin involves the following: 1) maintenance of an inactive, native pool in plasma at 2.3 M; 2) localization to the vascular endothelium through binding to glycosaminoglycans; 3) conformational activation; 4) ability to undergo a massive conformational rearrangement upon reaction with proteinase; and 5) release from glycosaminoglycan upon formation of complex with proteinase. The complexity of the role of antithrombin in hemostasis is illustrated by the wide range of antithrombin mutations that lead to thromboembolic disorders (2).…”

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

“…1a) allow the aberrant opening of the A-sheet, with the risk of the insertion, into its lower half, of the reactive loop of another molecule to give intermolecular linkage and polymerization of the serpin. Even minor changes in the shutter region of ␣ 1 -antitrypsin (8) and antichymotrypsin (9) result in their polymerization and intracellular aggregation with consequent lung and liver disease and similarly with C1-inhibitor (10) and antithrombin mutations (11) resulting in angioedema and thrombosis. But the best example of the critical function of this region comes from recent investigations of a novel form of familial neurodegenerative disease due to the aggregation within neurons of a brain-specific serpin, neuroserpin (12).…”

Antithrombin Murcia (K241E) causing antithrombin deficiency: a possible role for altered glycosylation

“…Type II deficiency, with significant clinical heterogeneity, is further sub-classified on the basis of mutations that either alter the function of the reactive site, the heparinbinding site or have multiple or pleiotropic effects. 3 Research has provided information concerning the mechanisms responsible for antithrombin deficiency. Thus, the identification of missense mutations affecting mobile regions (mainly the hinges of the reactive center loop (RCL) or the region involved in the shutter-like opening of the main b-sheet) that caused oligomer formation and intracellular retention, revealed a new pathological mechanism causing antithrombin deficiency, including some cases of thrombosis within the group of conformational diseases.…”