Abstract
Integrin alpha v beta 6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete alpha v beta 6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of alpha v beta 6 center dot uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the beta-propeller region of integrin alpha-chain interacting with uPAR. Interaction of alpha v beta 6 center dot uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with alpha v beta 6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin alpha v beta 6 center dot uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management. (C) 2014 Elsevier Inc. All rights reserved.