Structure and binding interface of the cytosolic tails of ?x?2 integrin

Abstract

Background: Integrins are signal transducer proteins involved in a number of vital physiological processes including cell adhesion, proliferation and migration. Integrin molecules are hetero-dimers composed of two distinct subunits, ? and ?. In humans, 18 ? and 8 ? subunits are combined into 24 different integrin molecules. Each of the subunit comprises a large extracellular domain, a single pass transmembrane segment and a cytosolic tail (CT). The CTs of integrins are vital for bidirectional signal transduction and in maintaining the resting state of the receptors. A large number of intracellular proteins have been found to interact with the CTs of integrins linking integrins to the cytoskeleton. Methodology/Principal Findings: In this work, we have investigated structure and interactions of CTs of the leukocyte specific integrin ?X?2. We determined the atomic resolution structure of a myristoylated CT of ?X in perdeuterated dodecylphosphocholine (DPC) by NMR spectroscopy. Our results reveal that the 35-residue long CT of ?X adopts an ?-helical conformation for residues F4-N17 at the N-terminal region. The remaining residues located at the C-terminal segment of ?X delineate a long loop of irregular conformations. A segment of the loop maintains packing interactions with the helical structure by an extended non-polar surface of the ?X CT. Interactions between ?X and ?2 CTs are demonstrated by 15N-1H HSQC NMR experiments. We find that residues constituting the polar face of the helical conformation of ?X are involved in interactions with the N-terminal residues of ?2 CT. A docked structure of the CT complex indicates that a network of polar and/or salt-bridge interactions may sustain the heteromeric interactions. Conclusions/Significance: The current study provides important insights into the conservation of interactions and structures among different CTs of integrins. © 2012 Chua et al.