title: The Integrin Receptor in Biologically Relevant Bilayers: Insights from Molecular Dynamics Simulations.
abstract: Integrins are heterodimeric (αβ) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2-F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive. In this study an integrin/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics. The results of this study demonstrate the dynamic nature of the integrin receptor and suggest that the presence of the integrin receptor alters the lipid organization between the two leaflets of the bilayer. In particular, our results suggest elevated density of cholesterol and of phosphatidylserine lipids around the integrin/talin complex and a slowing down of lipids in an annulus of ~30 Å around the protein due to interactions between the lipids and the integrin/talin F2-F3 complex. This may in part regulate the interactions of integrins with other related proteins or integrin clustering thus facilitating signal transduction across cell membranes.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: Antreas C
authors.initials: AC
authors.lastname: Kalli
authors.affiliation: Department of Physics, Tampere University of Technology, P.O. Box 692, 33101, Tampere, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Rog
authors.affiliation: Department of Physics, Tampere University of Technology, P.O. Box 692, 33101, Tampere, Finland.|MEMPHYS - Center for Biomembrane Physics, University of Southern Denmark, 5230, Odense M, Denmark.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Vattulainen
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: Iain D
authors.initials: ID
authors.lastname: Campbell
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. mark.sansom@bioch.ox.ac.uk.
authors.forename: Mark S P
authors.initials: MSP
authors.lastname: Sansom
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D016608:Talin / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D039302:Integrin alphaVbeta3; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D021122:Protein Subunits; D016608:Talin; C057561:1-palmitoyl-2-oleoylphosphatidylethanolamine; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: Integrin; Lipid diffusion; Molecular dynamics simulations; Talin