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Structures and Interaction Analyses of the Integrin Alpha-M Beta-2 Cytoplasmic Tails
Structural highlights
DiseaseITAM_HUMAN Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:609939. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. FunctionITAM_HUMAN Integrin alpha-M/beta-2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles. It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin alpha-M/beta-2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. Publication Abstract from PubMedIntegrins are hetero-dimeric (alpha and beta subunits) signal transducer proteins involved in cell adhesions and migrations. The cytosolic tails of integrins are essential for transmitting bi-directional signaling and also implicated in maintaining the resting states of the receptors. In addition, cytosolic tails of integrin often undergo post-translation modification like phosphorylation. However, consequences of phosphorylation on the structures and interactions are not clear. The leukocyte-specific integrin alphaMbeta2 is essential for myeloid cell adhesion, phagocytosis and degranulation. In this work, we determine solution structures of myristoylated cytosolic tail of alphaM and a Ser phosphorylated variant in DPC micelles by NMR spectroscopy. Further, the interactions between alphaM tails, non phosphorylated and phosphorylated, with beta2 tail are investigated by NMR and fluorescence resonance energy transfer (FRET). The 3D structures of the 24-residue cytosolic tail of alphaM or phosphorylated alphaM are characterized by an N-terminal amphipathic helix and a loop at the C-terminus. The residues at the loop contain packing interactions with the hydrophobic face of the helix. 15N-1H HSQC experiments identify residues of alphaM and beta2 tails, those may be involved in formation of tail-tail hetero-complex. We have further examined interactions between myristoylated beta2 tail, in DPC micelles, with dansylated alphaM tail peptides by FRET. These studies reveal enhanced interactions between alphaM or phosphorylated alphaM tails with beta2 tail with Kd ~ 5.2+0.6 alphaM and Kd ~4.4+0.7 alphaM, respectively. Docked structures of tail/tail complexes delineated that alphaM/beta2 interface at the cytosolic region could be sustained by a network of polar interactions, ionic and/or hydrogen bonds. Structures and interaction analyses of the integrin alphaMbeta2 cytoplasmic tails.,Chua GL, Tang XY, Amalraj M, Tan SM, Bhattacharjya S J Biol Chem. 2011 Nov 3. PMID:22052909[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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