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Stretching of Twitchin Kinase
University of Illinois at Urbana Champaign, Urbana, IL, USA; Beckman Institute, Urbana, IL, USA.
Institute of Integrative Biology, University of Liverpool, Liverpool, IL, USA.
Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Vise andre og tillknytning
2012 (engelsk)Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 102, nr 3 Supplement 1, s. 361a-362aArtikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The giant proteins from the titin family, that form cytoskeletal filaments, have emerged as key mechanotransducers in the sarcomere. These proteins contain a conserved kinase region, which is auto-inhibited by a C-terminal tail domain. The inhibitory tail domain occludes the active sites of the kinases, thus preventing ATP from binding. It was proposed that through application of a force, such as that arising during muscle contraction, the inhibitory tail becomes detached, lifting inhibition. The force-sensing ability of titin kinase was demonstrated in AFM experiments and simulations [Puchner, et al., 2008, PNAS:105, 13385], which showed indeed that mechanical forces can remove the autoinhibitory tail of titin kinase. We report here steered molecular dynamics simulations (SMD) of the very recently resolved crystal structure of twitchin kinase, containing the kinase region and flanking fibronectin and immuniglobulin domains, that show a variant mechanism. Despite the significant structural and sequence similarity to titin kinase, the autoinhibitory tail of twitchin kinase remains in place upon stretching, while the N-terminal lobe of the kinase unfolds. The SMD simulations also show that the detachment and stretching of the linker between fibronectin and kinase regions, and the partial extension of the autoinhibitory tail, are the primary force-response. We postulate that this stretched state, where all structural elements are still intact, may represent the physiologically active state.

sted, utgiver, år, opplag, sider
St. Louis, MO, United States: Cell Press , 2012. Vol. 102, nr 3 Supplement 1, s. 361a-362a
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Identifikatorer
URN: urn:nbn:se:liu:diva-143666DOI: 10.1016/j.bpj.2011.11.1973ISI: 000321561202410OAI: oai:DiVA.org:liu-143666DiVA, id: diva2:1165125
Tilgjengelig fra: 2017-12-12 Laget: 2017-12-12 Sist oppdatert: 2017-12-21bibliografisk kontrollert

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