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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Motifs
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Amino Acid Sequence
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Cell Line, Tumor
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Conserved Sequence
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Crystallography, X-Ray
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Humans
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Hydrogen Bonding
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Hydrophobic and Hydrophilic Interactions
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Integrin beta1 / chemistry*
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Integrin beta1 / metabolism
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Intracellular Signaling Peptides and Proteins / chemistry*
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Intracellular Signaling Peptides and Proteins / metabolism
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KRIT1 Protein
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Membrane Proteins / chemistry*
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / chemistry*
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Microtubule-Associated Proteins / metabolism
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Models, Molecular
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Molecular Sequence Data
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Structure, Quaternary
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / metabolism
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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ITGB1BP1 protein, human
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Integrin beta1
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Intracellular Signaling Peptides and Proteins
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KRIT1 Protein
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KRIT1 protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Proto-Oncogene Proteins