title: The kindlin 3 pleckstrin homology domain has an essential role in lymphocyte function-associated antigen 1 (LFA-1) integrin-mediated B cell adhesion and migration.
abstract: The protein kindlin 3 is mutated in the leukocyte adhesion deficiency III (LAD-III) disorder, leading to widespread infection due to the failure of leukocytes to migrate into infected tissue sites. To gain understanding of how kindlin 3 controls leukocyte function, we have focused on its pleckstrin homology (PH) domain and find that deletion of this domain eliminates the ability of kindlin 3 to participate in adhesion and migration of B cells mediated by the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1). PH domains are often involved in membrane localization of proteins through binding to phosphoinositides. We show that the kindlin 3 PH domain has binding affinity for phosphoinositide PI(3,4,5)P3 over PI(4,5)P2. It has a major role in membrane association of kindlin 3 that is enhanced by the binding of LFA-1 to intercellular adhesion molecule 1 (ICAM-1). A splice variant, kindlin 3-IPRR, has a four-residue insert in the PH domain at a critical site that influences phosphoinositide binding by enhancing binding to PI(4,5)P2 as well as by binding to PI(3,4,5)P3. However kindlin 3-IPRR is unable to restore the ability of LAD-III B cells to adhere to and migrate on LFA-1 ligand ICAM-1, potentially by altering the dynamics or PI specificity of binding to the membrane. Thus, the correct functioning of the kindlin 3 PH domain is central to the role that kindlin 3 performs in guiding lymphocyte adhesion and motility behavior, which in turn is required for a successful immune response.
authors.affiliation: Leukocyte Adhesion Laboratory, Cancer Research United Kingdom London Research Institute, London WC2A 3LY, United Kingdom.
authors.forename: Rosie
authors.initials: R
authors.lastname: Hart
authors.forename: Paula
authors.initials: P
authors.lastname: Stanley
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D002448:Cell Adhesion / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary
chemical_list: C477322:FERMT3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D018799:Intercellular Adhesion Molecule-1
keywords: Adhesion; Cell Migration; Cell Signaling; Integrin; Kindlin; Lymphocyte; PH Domain; Receptors