4dx8
From Proteopedia
ICAP1 in complex with KRIT1 N-terminus
Structural highlights
Disease[KRIT1_HUMAN] Hereditary cerebral cavernous malformation. Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] Function[ITBP1_HUMAN] Regulates integrin signaling by binding to the ITGB1 cytoplasmic tail and preventing the activation of integrin alpha-5/beta-1 (heterodimer of ITGA5 and ITGB1) by talin or FERMT1. May play a role in the recruitment of ITGB1 to focal contacts during integrin-dependent cell adhesion.[REFERENCE:8] [KRIT1_HUMAN] Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.[2] [3] [4] [5] [REFERENCE:17] Publication Abstract from PubMedKRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in approximately 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 beta1 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 beta1 cytoplasmic tail to 2.54 and 3.0 A resolution (the resolutions at which I/sigmaI = 2 are 2.75 and 3.0 A, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that KRIT1 directly competes with integrin beta1 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. Mechanism for KRIT1 Release of ICAP1-Mediated Suppression of Integrin Activation.,Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ Mol Cell. 2013 Jan 9. pii: S1097-2765(12)01014-3. doi:, 10.1016/j.molcel.2012.12.005. PMID:23317506[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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