α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96

Integrins play important roles in regulating a diverse array of cellular functions crucial to the initiation, progression, and metastasis of tumors. Previous studies have shown that a majority of integrins are folded by the endoplasmic reticulum chaperone gp96. Here, we demonstrate that the dimerization of integrin αL and β2 is highly dependent on gp96. The αI domain (AID), a ligand binding domain shared by seven integrin α-subunits, is a critical region for integrin binding to gp96. Deletion of AID significantly reduced the interaction between integrin αL and gp96. Overexpression of AID intracellularly decreased surface expression of gp96 clients (integrins and Toll-like receptors) and cancer cell invasion. The α7 helix region is crucial for AID binding to gp96. A cell-permeable α7 helix peptide competitively inhibited the interaction between gp96 and integrins and blocked cell invasion. Thus, targeting the binding site of α7 helix of AID on gp96 is potentially a new strategy for treatment of cancer metastasis. Background: Integrins are chaperoned by gp96, but the binding region to gp96 remains unknown. Results: Deletion of α7 helix from αI domain of integrin abolished the interaction between integrin and gp96. Targeting this region by corresponding peptide blocked cell invasion. Conclusion: We successfully mapped the binding region of integrin to gp96. Significance: This study will facilitate the development of new cancer therapeutics.