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Title: Structure of the Shroom-Rho Kinase Complex Reveals a Binding Interface with Monomeric Shroom That Regulates Cell Morphology and Stimulates Kinase Activity

Shroom-mediated remodeling of the actomyosin cytoskeleton is a critical driver of cellular shape and tissue morphology that underlies the development of many tissues including the neural tube, eye, intestines, and vasculature. Shroom uses a conserved SD2 domain to direct the subcellular localization of Rho-associated kinase (Rock), which in turn drives changes in the cytoskeleton and cellular morphology through its ability to phosphorylate and activate non-muscle myosin II. Here in this paper, we present the structure of the human Shroom-Rock binding module, revealing an unexpected stoichiometry for Shroom in which two Shroom SD2 domains bind independent surfaces on Rock. Mutation of interfacial residues impaired Shroom-Rock binding in vitro and resulted in altered remodeling of the cytoskeleton and loss of Shroom-mediated changes in cellular morphology. In addition, we provide the first direct evidence that Shroom can function as a Rock activator. These data provide molecular insight into the Shroom-Rock interface and demonstrate that Shroom directly participates in regulating cytoskeletal dynamics, adding to its known role in Rock localization.
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1]
  1. Univ. of Pittsburgh, PA (United States). Dept. of Biological Sciences
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Dept. of Biology
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Pharmacology
Publication Date:
Report Number(s):
Journal ID: ISSN 0021-9258
Grant/Contract Number:
SC0012704; GM097204
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 49; Journal ID: ISSN 0021-9258
American Society for Biochemistry and Molecular Biology
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Shroom; serine/threonine-protein kinase; coiled-coil; Structural Biology; RhoA; Cell Contractility; cytoskeleton; Rock; X-ray crystallography
OSTI Identifier: