4jif
From Proteopedia
Co-crystal structure of ICAP1 PTB domain in complex with a KRIT1 peptide
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 PubMedIntegrin cytoplasmic domain-associated protein-1 (ICAP1) is a suppressor of integrin activation and directly binds to the cytoplasmic tail of beta1 integrins; its binding suppresses integrin activation by competition with talin. Krev/Rap1 interaction trapped-1 (KRIT1) releases ICAP1 suppression of integrin activation by sequestering ICAP1 away from integrin cytoplasmic tails. Here, the cocrystal structure of the PTB domain of ICAP1 in complex with a 29-amino-acid fragment (residues 170-198) of KRIT1 is presented to 1.7 A resolution [the resolution at which I/sigma(I) = 2.9 was 1.83 A]. In previous studies, the structure of ICAP1 with integrin beta1 was determined to 3.0 A resolution and that of ICAP1 with the N-terminal portion of KRIT1 (residues 1-198) was determined to 2.54 A resolution; therefore, this study provides the highest resolution structure yet of ICAP1 and allows further detailed analysis of the interaction of ICAP1 with its minimal binding region in KRIT1. Cocrystal structure of the ICAP1 PTB domain in complex with a KRIT1 peptide.,Liu W, Boggon TJ Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 May;69(Pt 5):494-8. doi:, 10.1107/S1744309113010762. Epub 2013 Apr 27. PMID:23695561[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
