Integrin,alphaIIbbeta3: Tale of Two Cytoplasmic Tails
Date of Completion
Chemistry, Biochemistry|Health Sciences, Pharmacy
Metazoans' cells adapt continuously in order to survive in a highly dynamic extracellular environment which requires a flow of information from extracellular matrix (ECM) to the cytoplasm. This process is controlled by integrins, the heterodimeric (α, β), glycoprotein adhesion receptors, which mediate cell-cell and cell-ECM interactions. The unique bidirectional flow of information through integrins involves ‘inside-out’ signals that allow them to interact with extracellular ligands, and ligand-dependent ‘outside-in’ signals that adjust the cellular response to cell adhesion. These integrins-ECM interactions are controlled by integrins' extracellular domains whereas integrins-cytoplasmic proteins interactions are controlled via their cytoplasmic tails (CTs). ^ This thesis focuses on the CTs of platelet integrin αllbβ 3 and their interaction with two different adapter proteins, skelemin and Shc. Phosphorylation of the integrin tails is considered to be one of the spatiotemporal, regulatory mechanisms. In case of β3CT, phosphorylation of the two tyrosine residues (747pY, 759pY) is crucial for controlling its function. Chapters 4 and 5 of this thesis deal with structural investigations of tyrosine phosphorylation of β3CT and its impact on the cross-talk with vascular endothelium growth factor receptor 2 (VEGFR2). ^ Chapter 6 concentrates on interaction between bi-phosphorylated β 3CT (747pY, 759pY) and an adaptor protein, Shc. Previous studies have shown that by specifically recognizing the tyrosine phosphorylated integrin β3, Shc mediates integrin ‘ outside-in’ signaling, although the structural basis of this interaction has remained nebulous. In chapter 6, we present the detailed structural analysis of Shc Phosphotyrosine Binding (PTB) domain in complex with the bi-phosphorylated β 3CT which reveals the first snapshot of an integrin cytoplasmic tail bound to a target for mediating the ‘outside-in’ signaling. ^ Finally, in Chapter 7, we decipher the interaction between CTs of α llbβ3 with a scaffold protein, skelemin. The two-tandem immunoglobulin C2-like repeats of skelemin (SklgC4, SklgC5, and SklgC45 when together) have been shown to interact with integrin β3CT. Our data shows that SklgC45 domains form a complex not only with integrin β 3CT but also, surprisingly, with the αllbCT. These data provide the first molecular insights into how skelemin may interact with integrins and regulate integrin-mediated signaling and cell spreading. ^
Deshmukh, Lalit, "Integrin,alphaIIbbeta3: Tale of Two Cytoplasmic Tails" (2010). Doctoral Dissertations. AAI3451403.