title: Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.
abstract: KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in ∼40% of autosomal-dominant cerebral cavernous malformations (CCMs), a disease occurring in up to 0.5% of the population. We show that KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1 (Integrin Cytoplasmic Associated Protein-1)-mediated modulation of "inside-out" activation. We present cocrystal structures of KRIT1 with ICAP1 and ICAP1 with integrin β1 cytoplasmic tail to 2.54 and 3.0 Å resolution (the resolutions at which I/σI = 2 are 2.75 and 3.0 Å, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that KRIT1 directly competes with integrin β1 to bind ICAP1, and that KRIT1 antagonizes ICAP1-modulated integrin activation using this site. We also find that KRIT1 contains an N-terminal Nudix domain, in a region previously designated as unstructured. We therefore provide insights to integrin regulation and CCM-associated KRIT1 function.
authors: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors: Weizhi
authors: W
authors: Liu
authors: Kyle M
authors: KM
authors: Draheim
authors: Rong
authors: R
authors: Zhang
authors: David A
authors: DA
authors: Calderwood
authors: Titus J
authors: TJ
authors: Boggon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D019012:Integrin beta1 / Q000737:chemistry* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D000075927:KRIT1 Protein; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108257:ITGB1BP1 protein, human; D019012:Integrin beta1; D047908:Intracellular Signaling Peptides and Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins