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Autophosphorylation is a mechanism of inhibition in twitchin kinase

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WILLIAMS, Rhys M., Barbara FRANKE, Mark WILKINSON, Jennifer R. FLEMING, Daniel J. RIGDEN, Guy M. BENIAN, Patrick A. EYERS, Olga MAYANS, 2018. Autophosphorylation is a mechanism of inhibition in twitchin kinase. In: Journal of molecular biology. 430(6), pp. 793-805. ISSN 0022-2836. eISSN 1089-8638. Available under: doi: 10.1016/j.jmb.2018.01.020

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

<rdf:RDF xmlns:dcterms="" xmlns:dc="" xmlns:rdf="" xmlns:bibo="" xmlns:dspace="" xmlns:foaf="" xmlns:void="" xmlns:xsd="" > <rdf:Description rdf:about=""> <dc:contributor>Eyers, Patrick A.</dc:contributor> <dcterms:isPartOf rdf:resource=""/> <dc:contributor>Franke, Barbara</dc:contributor> <dc:language>eng</dc:language> <dc:contributor>Williams, Rhys M.</dc:contributor> <bibo:uri rdf:resource=""/> <dc:contributor>Rigden, Daniel J.</dc:contributor> <dcterms:title>Autophosphorylation is a mechanism of inhibition in twitchin kinase</dcterms:title> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:creator>Fleming, Jennifer R.</dc:creator> <dcterms:available rdf:datatype="">2018-02-13T12:35:20Z</dcterms:available> <dcterms:issued>2018-03</dcterms:issued> <dc:creator>Eyers, Patrick A.</dc:creator> <dc:date rdf:datatype="">2018-02-13T12:35:20Z</dc:date> <dc:contributor>Fleming, Jennifer R.</dc:contributor> <dc:creator>Mayans, Olga</dc:creator> <dc:contributor>Mayans, Olga</dc:contributor> <dc:creator>Williams, Rhys M.</dc:creator> <dc:contributor>Wilkinson, Mark</dc:contributor> <dc:creator>Rigden, Daniel J.</dc:creator> <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> <dc:creator>Benian, Guy M.</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dspace:isPartOfCollection rdf:resource=""/> <dc:contributor>Benian, Guy M.</dc:contributor> <dc:creator>Wilkinson, Mark</dc:creator> <dc:creator>Franke, Barbara</dc:creator> </rdf:Description> </rdf:RDF>

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