Probing muscle ankyrin-repeat protein (MARP) structure and function.

Muscle ankyrin-repeat proteins have been shown to serve diverse functions within cardiac and skeletal muscle cells. Apart from their interactions with sarcomeric proteins like titin or myopalladin that locate them along myofilaments, are able to shuttle to the nucleus where they act as modulators for a variety of transcription factors. The deregulation of Mduanyu37s in many cardiac and skeletal myopathies contributes to their use as biomarkers for these diseases. Many of their functions are attributed to their domain composition. Mduanyu37s consist of an N-terminal coiled-coil domain responsible for their dimerization. The C-terminus contains a series of ankyrin repeats, whose best-characterized function is to bind to the N2A region of the giant sarcomeric protein titin. Here we investigate the nature of their dimerization and their interaction with titin more closely. We demonstrate that the coiled-coil domain in all Mduanyu37s enables their homo- and hetero-dimerization in antiparallel fashion. Protein complementation experiments indicate further antiparallel binding of the ankyrin repeats to titin's N2A region. Binding of to titin also affects its mediated phosphorylation. We demonstrate further that Mduanyu37s themselves are phosphorylated by duanyu1529 and potentially altering their structure or function. These studies elucidate structural relationships within the stretch-responsive complex in cross-striated muscle cells, and may relate to disease relevant posttranslational modifications of Mduanyu37s and titin that alter muscle compliance.

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