title: Regulation of actin catch-slip bonds with a RhoA-formin module.
abstract: The dynamic turnover of the actin cytoskeleton is regulated cooperatively by force and biochemical signaling. We previously demonstrated that actin depolymerization under force is governed by catch-slip bonds mediated by force-induced K113:E195 salt-bridges. Yet, the biochemical regulation as well as the functional significance of actin catch bonds has not been elucidated. Using AFM force-clamp experiments, we show that formin controlled by RhoA switches the actin catch-slip bonds to slip-only bonds. SMD simulations reveal that the force does not induce the K113:E195 interaction when formin binds to actin K118 and E117 residues located at the helical segment extending to K113. Actin catch-slip bonds are suppressed by single residue replacements K113E and E195K that interrupt the force-induced K113:E195 interaction; and this suppression is rescued by a K113E/E195K double mutant (E/K) restoring the interaction in the opposite orientation. These results support the biological significance of actin catch bonds, as they corroborate reported observations that RhoA and formin switch force-induced actin cytoskeleton alignment and that either K113E or E195K induces yeast cell growth defects rescued by E/K. Our study demonstrates how the mechano-regulation of actin dynamics is modulated by biochemical signaling molecules, and suggests that actin catch bonds may be important in cell functions.
authors.affiliation: Wallace H Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|Institute for Bioengineering and Biosciences, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
authors.forename: Cho-Yin
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Kuo-Kuang
authors.initials: KK
authors.lastname: Wen
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: McKane
authors.affiliation: Wallace H Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|Institute for Bioengineering and Biosciences, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Eskin
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City, IA, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rubenstein
authors.affiliation: Department of Bioengineering and Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA, USA.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ono
authors.affiliation: Wallace H Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|Institute for Bioengineering and Biosciences, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Wallace H Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University, Atlanta, GA, USA.|Institute for Bioengineering and Biosciences, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
authors.forename: Larry V
authors.initials: LV
authors.lastname: McIntire
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D005786:Gene Expression Regulation; D008239:Lysine / Q000235:genetics; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D020742:rhoA GTP-Binding Protein; D008239:Lysine