4DX8

ICAP1 in complex with KRIT1 N-terminus

Summary for 4DX8

• Entry DOI: 10.2210/pdb4dx8/pdb
• Related: 4DX9 4DXA
• Descriptor: Integrin beta-1-binding protein 1, Krev interaction trapped protein 1, BROMIDE ION, ... (4 entities in total)
• Functional Keywords: protein-protein complex, ptb domain, nudix fold, protein-protein interaction, membrane, nucleus, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 160560.78

Authors

Liu, W.,Draheim, K.,Zhang, R.,Calderwood, D.A.,Boggon, T.J. (deposition date: 2012-02-27, release date: 2013-01-09, Last modification date: 2024-02-28)

Primary citation

Liu, W.,Draheim, K.M.,Zhang, R.,Calderwood, D.A.,Boggon, T.J.
Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation.
Mol.Cell, 49:719-729, 2013

PubMed 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.

PubMed: 23317506
DOI: 10.1016/j.molcel.2012.12.005

Experimental method

X-RAY DIFFRACTION (2.54 Å)