4tkn
From Proteopedia
Structure of the SNX17 FERM domain bound to the second NPxF motif of KRIT1
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[SNX17_HUMAN] Critical regulator of endosomal recycling of numerous receptors, channels, and other transmembrane proteins. Binds to NPxY sequences in the cytoplasmic tails of target cargos. Plays a role in the sorting of endocytosed LRP1 and APP, and prevents their degradation. Required for maintenance of normal cell surface levels of APP and LRP1. Recycles internalized integrins ITGB1, ITGB5 and their associated alpha subunits, preventing them from lysosomal degradation. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)).[2] [3] [4] [5] [6] [7] [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.[8] [9] [10] [11] [REFERENCE:17] Publication Abstract from PubMedSorting nexin 17 (SNX17) is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. SNX17 localizes to early endosomes where it directly binds NPxY/F motifs in the cytoplasmic tails of its target receptors to mediate their rates of endocytic internalization, recycling, and/or degradation. SNX17 has also been implicated in mediating cell signaling and can interact with cytoplasmic proteins. Krev interaction trapped 1 (KRIT1), a cytoplasmic adaptor protein associated with cerebral cavernous malformations (CCM), has previously been shown to interact with SNX17. Here, we demonstrate that SNX17 indeed binds directly to KRIT1 and map the binding to the second Asn-Pro-x-Tyr/Phe (NPxY/F) motif in KRIT1. We further characterize the interaction as being mediated by the FERM domain of SNX17. We present the co-crystal structure of SNX17-FERM with the KRIT1-NPxF2 peptide to 3.0 A resolution, and demonstrate that the interaction is highly similar in structure and binding affinity to that between SNX17 and p-selectin. We verify the molecular details of the interaction by site directed mutagenesis and pull down assay, and thereby confirm that the major binding site for SNX17 is confined to the NPxF2 motif in KRIT1. Taken together, our results verify a direct interaction between SNX17 and KRIT1 and classify KRIT1 as a SNX17 binding partner. Structural determinants for binding of Sorting Nexin 17 (SNX17) to the cytoplasmic adaptor protein Krev Interaction Trapped 1 (KRIT1)*,Stiegler AL, Zhang R, Liu W, Boggon TJ J Biol Chem. 2014 Jul 24. pii: jbc.M114.584011. PMID:25059659[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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