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Investigation of calmodulin‐like and rod domain mutations suggests common molecular mechanism for α‐actinin‐1‐linked congenital macrothrombocytopenia
Author(s) -
O'Sullivan Leanne Rose,
Ajaykumar Amarendra Praburam,
Dembicka Kornelia Maria,
Murphy Aidan,
Grennan Eamonn Paul,
Young Paul William
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13562
Subject(s) - calmodulin , mutation , mechanism (biology) , genetics , chemistry , microbiology and biotechnology , biology , biochemistry , gene , physics , enzyme , quantum mechanics
Actinin‐1 mutations cause dominantly inherited congenital macrothrombocytopenia ( CMTP ), with mutations in the actin‐binding domain increasing actinin's affinity for F‐actin. In this study, we examined nine CMTP ‐causing mutations in the calmodulin‐like and rod domains of actinin‐1. These mutations increase, to varying degrees, actinin's ability to bundle actin filaments in vitro . Mutations within the calmodulin‐like domain decrease its thermal stability slightly but do not dramatically affect calcium binding, with mutant proteins retaining calcium‐dependent regulation of filament bundling in vitro . The G764S and E769K mutations increase cytoskeletal association of actinin in cells, and all mutant proteins colocalize with F‐actin in cultured HeLa cells. Thus, CMTP ‐causing actinin‐1 mutations outside the actin‐binding domain also increase actin association, suggesting a common molecular mechanism underlying actinin‐1 related CMTP .