LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex.
Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration.
Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK.
Thomas
T
Zacharchenko
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Xiaolan
X
Qian
School of Biosciences, University of Kent, Kent, Canterbury, CT2 7NJ, UK.
Benjamin T
BT
Goult
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Devina
D
Jethwa
Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK.
Teresa B
TB
Almeida
Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Christoph
C
Ballestrem
Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
David R
DR
Critchley
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Douglas R
DR
Lowy
Institute of Integrative Biology, University of Liverpool, BioSciences Building, Crown Street, Liverpool L69 7ZB, UK. Electronic address: igb2@liv.ac.uk.
Igor L
IL
Barsukov
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D016608:Talin / Q000737:chemistry* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism
C430864:DLC-1 (deleted in liver cancer) protein, mouse; D020690:GTPase-Activating Proteins; D016608:Talin; D025521:Tumor Suppressor Proteins; C496077:Tln1 protein, mouse