Grant: $189,438 - National Institutes of Health - Jul. 16, 2009
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Award Description: The family of heterodimeric integrin cell adhesion receptors regulates cell migration, survival, and differentiation in metazoa by responding to intra- and extracellular signals in inside-out and outside-in signaling pathways, respectively. Integrin alphaIIbbeta3, the primary adhesion receptor of blood platelets, mediates platelet aggregation by binding to the multivalent blood protein fibrinogen. It is essential to both the arrest of bleeding at sites of vascular injury and pathological thrombosis culminating in heart attack and troke. An understanding of the signaling mechanism of integrins, representing our overarching goal, therefore provides insight into fundamental principles underlying one of the leading causes of death in the western world. Recently, an integrin transmembrane signaling hypothesis was proposed by us based upon the structures of its two individual alphaIIb and beta3 transmembrane segments, and alphaIIbbeta3 transmembrane complex as well as lipid embedding estimates and structure-based site-directed mutagenesis. Integrin alphaIIbbeta3 bi-directional signaling can be explained by the unique structure of its transmembrane complex, its ectodomain conformation-dependent stabilization and intracellular ligand-dependent structural interferences. To further understand transmembrane signaling, the present grant supplement aims at characterizing the relationship of the intracellular ligands with the transmembrane region on a structural and dynamic level to understand the mechanism of signal relay. In addition, the threshold of integrin signaling (activation) may be modulated by the alpha-beta transmembrane affinity and may vary between different human integrin receptors. A comparison of integrin alpha-beta transmembrane complex structures and evaluation of relative alpha-beta ?transmembrane affinities is pursued to understand key structural factors that determine the transmembrane signaling event. A comprehensive understanding of integrin transmembrane signaling at atomic resolution lays the foundation for therapeutic interventions aimed at controlling human diseases such as heart attack and stroke by drugs.
Project Description: The purpose of the Administrative Supplement is to reveal additional mechanistic details of integrin transmembrane signaling. Specifically, ?/? transmembrane affinities between different human integrin receptors are evaluated and role of individual amino acids in the membrane embedding of integrin transmembrane segments is evaluated. We have prepared constructs incorporating selected point mutations and currently evaluate expression and NMR sample conditions to characterize their effects on structure, dynamics and membrane embedding.
Infrastructure Description: N/A
Jobs Summary: Scientific/ Technical Professionals and Staff (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 16, 2009. Help expand these official descriptions using the wiki below.