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

Zalewski, Jenna K. and Mo, Joshua H. and Heber, Simone and Heroux, Annie and Gardner, Richard G. and Hildebrand, Jeffrey D. and VanDemark, Andrew P. (2016) Structure of the Shroom-Rho Kinase Complex Reveals a Binding Interface with Monomeric Shroom That Regulates Cell Morphology and Stimulates Kinase Activity. Journal of Biological Chemistry, 291 (49). pp. 25364-25374. ISSN 0021-9258

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Abstract

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, 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. Additionally, 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zalewski, Jenna K.
Mo, Joshua H.
Heber, Simone
Heroux, Annie
Gardner, Richard G.
Hildebrand, Jeffrey D.
VanDemark, Andrew P.andyv@pitt.edu
Date: 10 October 2016
Date Type: Publication
Journal or Publication Title: Journal of Biological Chemistry
Volume: 291
Number: 49
Publisher: American Society for Biochemistry and Molecular Biology
Page Range: pp. 25364-25374
DOI or Unique Handle: 10.1074/jbc.m116.738559
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Refereed: Yes
ISSN: 0021-9258
Official URL: http://dx.doi.org/10.1074/jbc.M116.738559
Article Type: Research Article
Date Deposited: 19 Jun 2020 13:18
Last Modified: 19 Jun 2020 13:18
URI: http://d-scholarship.pitt.edu/id/eprint/39128

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