@article{Williams2018-03Autop-41302,
  year={2018},
  doi={10.1016/j.jmb.2018.01.020},
  title={Autophosphorylation is a mechanism of inhibition in twitchin kinase},
  number={6},
  volume={430},
  issn={0022-2836},
  journal={Journal of molecular biology},
  pages={793--805},
  author={Williams, Rhys and Franke, Barbara and Wilkinson, Mark and Fleming, Jennifer S. and Rigden, Daniel J. and Benian, Guy M. and Eyers, Patrick A. and Mayans, Olga}
}

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    <dc:contributor>Eyers, Patrick A.</dc:contributor>
    <dc:creator>Mayans, Olga</dc:creator>
    <dc:contributor>Mayans, Olga</dc:contributor>
    <dc:creator>Benian, Guy M.</dc:creator>
    <dc:contributor>Rigden, Daniel J.</dc:contributor>
    <dc:creator>Rigden, Daniel J.</dc:creator>
    <dc:contributor>Franke, Barbara</dc:contributor>
    <dc:creator>Eyers, Patrick A.</dc:creator>
    <dc:creator>Williams, Rhys</dc:creator>
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    <dcterms:title>Autophosphorylation is a mechanism of inhibition in twitchin kinase</dcterms:title>
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    <dc:creator>Wilkinson, Mark</dc:creator>
    <dc:contributor>Fleming, Jennifer S.</dc:contributor>
    <dc:contributor>Benian, Guy M.</dc:contributor>
    <dc:creator>Franke, Barbara</dc:creator>
    <dc:contributor>Wilkinson, Mark</dc:contributor>
    <dcterms:issued>2018-03</dcterms:issued>
    <dcterms:abstract xml:lang="eng">Titin-like kinases are muscle-specific kinases that regulate mechanical sensing in the sarcomere. Twitchin kinase (TwcK) is the best-characterized member of this family, both structurally and enzymatically. TwcK activity is auto-inhibited by a dual intrasteric mechanism, in which N- and C-terminal tail extensions wrap around the kinase domain, blocking the hinge region, the ATP binding pocket and the peptide substrate binding groove. Physiologically, kinase activation is thought to occur by a stretch-induced displacement of the inhibitory tails from the kinase domain. Here, we now show that TwcK inhibits its catalysis even in the absence of regulatory tails, by undergoing auto-phosphorylation at mechanistically important elements of the kinase fold. Using mass spectrometry, site-directed mutagenesis and catalytic assays on recombinant samples we identify residues T212, T301, T316 and T401 as primary auto-phosphorylation sites in TwcK in vitro. Taken together, our results suggest that residue T316, located in the peptide substrate binding P+1 loop, is the dominantly regulatory site in TwcK. Based on these findings, we conclude that TwcK is regulated through a triple inhibitory mechanism consisting of phosphorylation as well as intrasteric blockage, which is responsive not only to mechanical cues but also to biochemical modulation. This implies that mechanically stretched conformations of TwcK do not necessarily correspond to catalytically active states, as previously postulated. This further suggests a phosphorylation-dependent desensitization of the TwcK-mediated mechanoresponse of the sarcomere in vivo.</dcterms:abstract>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-02-13T12:35:20Z</dcterms:available>
    <dc:contributor>Williams, Rhys</dc:contributor>
    <dc:creator>Fleming, Jennifer S.</dc:creator>
    <dc:language>eng</dc:language>
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    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-02-13T12:35:20Z</dc:date>
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