2. Academic Validation
  3. Structure and regulation of the myotonic dystrophy kinase-related Cdc42-binding kinase

Structure and regulation of the myotonic dystrophy kinase-related Cdc42-binding kinase

  • Structure. 2023 Apr 6;31(4):435-446.e4. doi: 10.1016/j.str.2023.02.002.
Linda Truebestein 1,  Sumire Antonioli 2,  Elisabeth Waltenberger 1,  Charlotte Gehin 3,  Anne-Claude Gavin 4,  Thomas A Leonard 5
Affiliations

Affiliations

  • 1 Department of Structural and Computational Biology, Max Perutz Labs, Campus Vienna Biocenter 5, 1030 Vienna, Austria; Department of Medical Biochemistry, Medical University of Vienna, 1090 Vienna, Austria.
  • 2 Department of Structural and Computational Biology, Max Perutz Labs, Campus Vienna Biocenter 5, 1030 Vienna, Austria; Department of Medical Biochemistry, Medical University of Vienna, 1090 Vienna, Austria; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, 1030 Vienna, Austria.
  • 3 European Molecular Biology Laboratory, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany; École Polytechnique Fédérale de Lausanne (EPFL), AI 1108, Station 19, 1015 Lausanne, Switzerland.
  • 4 European Molecular Biology Laboratory, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany; University of Geneva, Department of Cell Physiology and Metabolism, CMU Rue Michel-Servet 1, 1211 Genève 4, Switzerland.
  • 5 Department of Structural and Computational Biology, Max Perutz Labs, Campus Vienna Biocenter 5, 1030 Vienna, Austria; Department of Medical Biochemistry, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: thomas.leonard@meduniwien.ac.at.
PMID: 36854301 DOI: 10.1016/j.str.2023.02.002
Abstract

Protein kinases of the dystonia myotonica protein kinase (DMPK) family are critical regulators of actomyosin contractility in cells. The DMPK kinase MRCK1 is required for the activation of Myosin, leading to the development of cortical tension, apical constriction, and early gastrulation. Here, we present the structure, conformation, and membrane-binding properties of Caenorhabditis elegans MRCK1. MRCK1 forms a homodimer with N-terminal kinase domains, a parallel coiled coil of 55 nm, and a C-terminal tripartite module of C1, pleckstrin homology (PH), and citron homology (CNH) domains. We report the high-resolution structure of the membrane-binding C1-PH-CNH module of MRCK1 and, using high-throughput and conventional liposome-binding assays, determine its binding to specific Phospholipids. We further characterize the interaction of the C-terminal CRIB motif with Cdc42. The length of the coiled-coil domain of DMPK kinases is remarkably conserved over millions of years of evolution, suggesting that they may function as molecular rulers to position kinase activity at a fixed distance from the membrane.

Keywords

Cdc42; DMPK; MRCK; citron homology domain; coiled-coil; kinase; lipid; membrane; molecular ruler.

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