title: Membrane binding of the N-terminal ubiquitin-like domain of kindlin-2 is crucial for its regulation of integrin activation.
abstract: Kindlin-2 belongs to an emerging class of regulators for heterodimeric (α/β) integrin adhesion receptors. By binding to integrin β cytoplasmic tail via its C-terminal FERM-like domain, kindlin-2 promotes integrin activation. Intriguingly, this activation process depends on the N terminus of kindlin-2 (K2-N) that precedes the FERM domain. The molecular function of K2-N is unclear. We present the solution structure of K2-N, which displays a ubiquitin fold similar to that observed in kindlin-1. Using chemical shift mapping and mutagenesis, we found that K2-N contains a conserved positively charged surface that binds to membrane enriched with negatively charged phosphatidylinositol-(4,5)-bisphosphate. We show that while wild-type kindlin-2 is capable of promoting integrin activation, such ability is significantly reduced for its membrane-binding defective mutant. These data suggest a membrane-binding function of the ubiquitin-like domain of kindlin-2, which is likely common for all kindlins to promote their localization to the plasma membrane and control integrin activation.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: H Dhanuja
authors.initials: HD
authors.lastname: Perera
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jamila
authors.initials: J
authors.lastname: Hirbawi
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D013499:Surface Properties; D016608:Talin / Q000737:chemistry
chemical_list: C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin
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