https://www.auburn.edu/academic/classes/biol/6190/refs/L04/1-s2.0-S0092867402009716-main.pdf

Integrins: Bidirectional, Allosteric Signaling Machines

Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.

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Cell migration: integrating signals from front to back.

Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen—the prototypical collagen fibril—has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.

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Collagen Structure and Stability

The structural basis for the divalent cation-dependent binding of heterodimeric alphabeta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alphaV and beta3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in betaA, the ligand-binding domain of beta3; in the complex, betaA acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alphaV relative to beta3.

Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand

Integrins are cell adhesion molecules that mediate cell-cell, cell– extracellular matrix, and cell-pathogen interactions. They play critical roles for the immune system in leukocyte trafficking and migration, immunological synapse formation, costimulation, and phagocytosis. Integrin adhesiveness can be dynamically regulated through a process termed inside-out signaling. In addition, ligand binding transduces signals from the extracellular domain to the cytoplasm in the classical outside-in direction. Recent structural, biochemical, and biophysical studies have greatly advanced our understanding of the mechanisms of integrin bidirectional signaling across the plasma membrane. Large-scale reorientations of the ectodomain of up to 200 ˚ A couple to conformational change in ligand-binding sites and are linked to changes in α and β subunit transmembrane domain association. In this review, we focus on integrin structure as it relates to affinity modulation, ligand binding, outside-in signaling, and cell surface distribution dynamics.

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Structural Basis of Integrin Regulation and Signaling

L'invention concerne des peptides, des fragments et des variantes de collagene capables d'interagir et/ou de se lier avec l'integrine α2β1, l'integrine α1β1, et/ou le recepteur GpVI des plaquettes. Ces peptides, des mimetiques de ces peptides et des substances liant ces peptides sont utiles dans la modulation plaquettaire et autres fonctions cellulaires, notamment l'agregation et l'activation.

Peptides de collagene et leurs utilisations

L'invention concerne la structure cristalline d'un peptide de collagene formant un complexe avec le domaine I de l'integrine α2. Les coordonnees de la structure cristalline sont utiles pour elaborer de nouvelles molecules qui peuvent etre testees afin de determiner leur liaison au recepteur et a d'autres domaines I et de preference leur capacite a inhiber la liaison du domaine I a un ligand et la fonction du domaine I. Des regions du domaine I qui subissent un changement de conformation lorsqu'elle se lient a un ligand sont egalement identifiees et utilisees comme cibles pour des molecules de liaison telles que des anticorps. L'invention concerne egalement des molecules qui inhibent la fonction de polypeptides comprenant des domaines I et qui presentent un potentiel therapeutique pour un certain nombre de maladies et de troubles.

Michael J. Barnes

Papers

Peptides de collagene et leurs utilisations

Structure cristalline d'une interaction recepteur/peptide permettant d'identifier des inhibiteurs