Nanyang Technological University, School of Biological Sciences
Antimicrobial Drug Design, Discovery and Characterization, Molecular Mechanism of Signalling of Cell adhesion Proteins
Analyses of Multi-Protein Complexes in Beta-2 Integrin Signaling
Abstract:Integrins, hetero-dimeric (alpha and beta subunits) signal-transducer proteins, are essential for cell adhesion and migration. Beta cytosolic tails (beta-CTs) of integrins interact with a number of cytosolic proteins including talin, Dok1, 14-3-3z and filamin. The formation of multi-protein complexes with beta-CTs is involved in the activation and regulation of integrins. However, the sequence of event of interactions remains unclear. The leukocyte-specific beta2 integrins are essential for leukocyte trafficking, phagocytosis, antigen-presentation and proliferation. We are examining and characterizing molecular interactions of beta2-CT and alpha CTs with cytosolic proteins, in binary and ternary complexes by NMR and biophysical methods. We find novel interactions that may have strong implications in integrin signalling mechanism. Our current results demonstrated (1) talin head domain and 14-3-3z form a stable ternary complex with phosphorylated beta2-CT, (2) Dok1, a negative regulator of activation, binds to a non-canonical motif in beta2-CT, (3) direct interactions between 14-3-3z and Dok1 or 14-3-3z/filamin modulate recruitment of positive and negative regulator to the b2-CT. These observations help in building new models of regulation of integrins.