Twitchin kinase inhibits muscle activity

• Authors: Yohei Matsunaga, Emory University; Hyundoo Hwang, Georgia Institute of Technology; Barbara Franke, Emory University; Rhys Williams, Emory University; McKenna Penley, Emory University; Hiroshi Qadota, Emory University; Hong Yi, University of Konstanz; Levi Morran, Emory University; Hang Lu, Georgia Institute of Technology; Olga Mayans, Emory University; Guy Benian, Emory University
• Journal Title: Molecular Biology of the Cell
• Volume: Volume 28, Number 12
• Publisher: American Society for Cell Biology | 2017-06-15, Pages 1591-1600
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1091/mbc.E16-10-0707
• Subjects: Health Sciences, Pathology; Engineering, Biomedical; Biology, Physiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; SMALL-ANGLE SCATTERING; CAMP-DEPENDENT KINASE; CAENORHABDITIS-ELEGANS; PROTEIN-KINASE; SYNAPTIC FUNCTION; UNC-22 GENE; DOMAINS; OBSCURIN; TITIN; PHOSPHORYLATION

Abstract

© 2017 Matsunaga et al. 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.