title: A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking.
abstract: Integrin αvβ6 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 αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·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 αvβ6 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 αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia; ARC Centre of Excellence in Bioinformatics, Macquarie University, Sydney, NSW, Australia.
authors.forename: Gopichandran
authors.initials: G
authors.lastname: Sowmya
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia; ARC Centre of Excellence in Bioinformatics, Macquarie University, Sydney, NSW, Australia.
authors.forename: Javed Mohammed
authors.initials: JM
authors.lastname: Khan
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Samyuktha
authors.initials: S
authors.lastname: Anand
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Seong Beom
authors.initials: SB
authors.lastname: Ahn
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Baker
authors.affiliation: Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia; ARC Centre of Excellence in Bioinformatics, Macquarie University, Sydney, NSW, Australia; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: shoba.ranganathan@mq.edu.au.
authors.forename: Shoba
authors.initials: S
authors.lastname: Ranganathan
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040901:Proteomics; D055293:Receptors, Urokinase Plasminogen Activator / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D055293:Receptors, Urokinase Plasminogen Activator; C073878:integrin alphavbeta6
keywords: Integrin heterodimer; Integrin αvβ6; Molecular docking; Protein–protein interactions; Structural modelling; uPAR