Murphy, ACH;Lindsay, AJ;McCaffrey, MW;Djinovic-Carugo, K;Young, PW

2016

March

Febs Letters

Congenital macrothrombocytopenia-linked mutations in the actin-binding domain of alpha-actinin-1 enhance F-actin association

Published

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FOCAL SEGMENTAL GLOMERULOSCLEROSIS CALPONIN HOMOLOGY DOMAINS MUSCLE ALPHA-ACTININ CRYSTAL-STRUCTURE CROSS-LINKING DYSTROPHIN IDENTIFICATION MECHANISM CONFORMATION AFFINITY

590

685

695

Mutations in the actin cross-linking protein actinin-1 were recently linked to dominantly inherited congenital macrothrombocytopenia. Here, we report that several disease-associated mutations that are located within the actinin-1 actin-binding domain cause increased binding of actinin-1 to actin filaments and enhance filament bundling in vitro. These actinin-1 mutants are also more stably associated with the cytoskeleton in cultured cells, as assessed by biochemical fractionation and fluorescence recovery after photobleaching experiments. For two mutations the disruption of contacts between the calponin homology domains within the actinin actin-binding domain may explain increased filament binding - providing mechanistic and structural insights into the basis of actinin-1 dysfunction in congenital macrothrombocytopenia.

HOBOKEN

0014-5793

10.1002/1873-3468.12101