3t9k
Crystal Structure of ACAP1 C-portion mutant S554D fused with integrin beta1 peptide
Structural highlights
FunctionITB1_HUMAN Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. Isoform beta-1B interferes with isoform beta-1A resulting in a dominant negative effect on cell adhesion and migration (in vitro). In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. When associated with alpha-7/beta-1 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and GNB2L1/RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis.[1] [2] [3] ACAP1_HUMAN GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6) required for clathrin-dependent export of proteins from recycling endosomes to trans-Golgi network and cell surface. Required for regulated export of ITGB1 from recycling endosomes to the cell surface and ITGB1-dependent cell migration.[4] [5] [6] [7] [8] Publication Abstract from PubMedCoat complexes sort protein cargoes into vesicular transport pathways. An emerging class of coat components has been the GAPs (GTPase activating proteins) that act on the ARF (ADP-Ribosylation factor) family of small GTPases. ACAP1 (ArfGAP with Coil coil, Ankyrin repeat, and PH domain protein 1) is an ARF6 GAP that also acts as a key component of a recently defined clathrin complex for endocytic recycling. Phosphorylation by Akt has been shown to enhance cargo binding by ACAP1 in explaining how integrin recycling is an example of regulated transport. We now shed further mechanistic insights into how this regulation is achieved at the level of cargo binding by ACAP1. We initially define a critical sequence in the cytoplasmic domain of integrin beta1 recognized by ACAP1, and show that this sequence acts as a recycling sorting signal. We then pursue a combination of structural, modeling and functional studies, which suggest that phosphorylation of ACAP1 relieves a localized mechanism of auto-inhibition in regulating cargo binding. Thus, we have elucidated a key regulatory juncture that controls integrin recycling, and also advanced the understanding of how regulated cargo binding can lead to regulated transport. Mechanistic insights into regulated cargo binding by ACAP1.,Bai M, Pang X, Lou J, Zhou Q, Zhang K, Ma J, Li J, Sun F, Hsu V J Biol Chem. 2012 May 29. PMID:22645133[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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