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Mol Biol Cell. 2017 Jun 15;28(12):1591-1600. doi: 10.1091/mbc.E16-10-0707. Epub 2017 Apr 20.

Twitchin kinase inhibits muscle activity.

Author information

1
Department of Pathology, Emory University, Atlanta, GA 30322.
2
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
3
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
4
Department of Biology, Emory University, Atlanta, GA 30322.
5
Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta, GA 30322.
6
Department of Pathology, Emory University, Atlanta, GA 30322 pathgb@emory.edu.

Abstract

Muscle sarcomeres contain giant polypeptides composed of multiple immunoglobulin and fibronectin domains and one or two protein kinase domains. Although binding partners for a number of this family's kinase domains have been identified, the catalytic necessity of these kinase domains remains unknown. In addition, various members of this kinase family are suspected pseudokinases with no or little activity. Here we address catalytic necessity for the first time, using the prototypic invertebrate representative twitchin (UNC-22) from Caenorhabditis elegans In in vitro experiments, change of a conserved lysine (K) that is involved in ATP coordination to alanine (A) resulted in elimination of kinase activity without affecting the overall structure of the kinase domain. The same mutation, unc-22(sf21), was generated in the endogenous twitchin gene. The unc-22(sf21) worms have well-organized sarcomeres. However, unc-22(sf21) mutants move faster than wild-type worms and, by optogenetic experiments, contract more. Wild-type nematodes exhibited greater competitive fitness than unc-22(sf21) mutants. Thus the catalytic activity of twitchin kinase has a role in vivo, where it inhibits muscle activity and is likely maintained by selection.

PMID:
28428253
PMCID:
PMC5469603
DOI:
10.1091/mbc.E16-10-0707
[Indexed for MEDLINE]
Free PMC Article

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