Investigation of calmodulin‐like and rod domain mutations suggests common molecular mechanism for α‐actinin‐1‐linked congenital macrothrombocytopenia
O'Sullivan, Leanne Rose; Ajaykumar, Praburam Amarendra; Dembicka, Kornelia Maria; Murphy, Aidan; Grennan, Eamonn Paul; Young, Paul W.
Date:
2019-07-31
Copyright:
© 2019, Federation of European Biochemical Societies. Published by John Wiley & Sons, Inc. This is the peer reviewed version of the following article: O'Sullivan, L. R., Ajaykumar, P. A., Dembicka, K. M., Murphy, A., Grennan, E. P. and Young, P. W. (2019) 'Investigation of calmodulin‐like and rod domain mutations suggests common molecular mechanism for α‐actinin‐1‐linked congenital macrothrombocytopenia', FEBS Letters. doi: 10.1002/1873-3468.13562, which has been published in final form at https://doi.org/10.1002/1873-3468.13562. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
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Access to this article is restricted until 12 months after publication by request of the publisher.
Restriction lift date:
2020-07-31
Citation:
O'Sullivan, L. R., Ajaykumar, P. A., Dembicka, K. M., Murphy, A., Grennan, E. P. and Young, P. W. (2019) 'Investigation of calmodulin‐like and rod domain mutations suggests common molecular mechanism for α‐actinin‐1‐linked congenital macrothrombocytopenia', FEBS Letters. doi: 10.1002/1873-3468.13562
Abstract:
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.
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