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Modeling ATM mutant proteins from missense changes confirms retained kinase activity by Giancarlo Barone; Alix Groom; Anne Reiman; Venkataramanan Srinivasan; Philip J. Byrd; A. Malcolm R. Taylor is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Modeling ATM mutant proteins from missense changes confirms retained kinase activity about?

Ataxia-telangiectasia mutated (ATM) is the gene mutated in the cancer-predisposing disorder ataxiatelangiectasia (A-T). We modeled ATM sequence variants identified in UK A-T patients to determine the stability and kinase activity of the resulting proteins as well as the distribution of these mutations across the coding region. Of 20 missense changes modeled, 10 proteins showed ATM kinase activity and 10 showed none. In the majority of cases the mutant ATM protein was unstable, although this was variable. Reduction in ATM kinase activity can result either from the presence of low levels of unstable mutant protein with relatively normal specific kinase activity or from stable mutant protein with deficient ATM kinase activation. Indeed, ATM mutant proteins without kinase activity toward downstream targets were still able to autophosphorylate on serine 1981, although in a much less efficient manner, suggesting that this was not sufficient for ATM activation. In terms of function, green fluorescent protein (GFP)-tagged kinase inactive ATM proteins could form ionizing radiation (IR)-induced foci (IRIF), at least temporarily, which colocalized with the DNA doublestrand break (DSB) marker

Who reads Modeling ATM mutant proteins from missense changes confirms retained kinase activity?

Author

Giancarlo Barone; Alix Groom; Anne Reiman; Venkataramanan Srinivasan; Philip J. Byrd; A. Malcolm R. Taylor

Publisher

Hindawi Limited

Published

2009

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)