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Titolo:
Binding of a fibrinogen mimetic stabilizes integrin alpha IIb beta 3's open conformation
Autore:
Hantgan, RR; Rocco, M; Nagaswami, C; Weisel, JW;
Indirizzi:
Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA Wake Forest Univ Winston Salem NC USA 27157 , Winston Salem, NC 27157 USA CBA, IST, Ist Nazl Ric Canc, UO Biol Strutturale, I-16132 Genoa, Italy CBA Genoa Italy I-16132 Canc, UO Biol Strutturale, I-16132 Genoa, Italy Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Dev Biol, Philadelphia, PA 19104 USA
Titolo Testata:
PROTEIN SCIENCE
fascicolo: 8, volume: 10, anno: 2001,
pagine: 1614 - 1626
SICI:
0961-8368(200108)10:8<1614:BOAFMS>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
GLYCOPROTEIN-IIB-IIIA; ARG-GLY-ASP; PROTEIN-DRIVEN CRYSTALLIZATION; BETA-PROPELLER DOMAIN; LIGAND-BINDING; GAMMA-CHAIN; ELECTRON-MICROSCOPY; CELL-ADHESION; STRUCTURAL BASIS; GPIIB-IIIA;
Keywords:
integrins; fibrinogen receptor; light scattering; analytical ultracentrifugation; electron microscopy; molecular modeling; ligand binding; hydrodynamics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
88
Recensione:
Indirizzi per estratti:
Indirizzo: Hantgan, RR Wake Forest Univ, Sch Med, Dept Biochem, Med Ctr Blvd, WinstonSalem, NC 27157 USA Wake Forest Univ Med Ctr Blvd Winston Salem NC USA 27157 7 USA
Citazione:
R.R. Hantgan et al., "Binding of a fibrinogen mimetic stabilizes integrin alpha IIb beta 3's open conformation", PROTEIN SCI, 10(8), 2001, pp. 1614-1626

Abstract

The platelet integrin alpha IIb beta3 is representative of a class of heterodimeric receptors that upon activation bind extracellular macromolecular ligands and form signaling clusters. This study examined how occupancy of alpha IIb beta3's fibrinogen binding site affected the receptor's solution structure and stability. Eptifibatide, an integrin antagonist developed to treat cardiovascular disease, served as a high-affinity, monovalent model ligand with fibrinogen-like selectivity for alpha IIb beta3 Eptifibatide binding promptly and reversibly perturbed the conformation of the alpha IIb beta3 complex. Ligand-specific decreases in its diffusion and sedimentation coefficient were observed at near-stoichiometric eptifibatide concentrations,in contrast to the receptor-perturbing effects of RGD ligands that we previously observed only at a 70-fold molar excess. Eptifibatide promoted alphaIIb beta3 dimerization 10-fold more effectively than less selective RGD ligands, as determined by sedimentation equilibrium. Eptifibatide-bound integrin receptors displayed an ectodomain separation and enhanced assembly of dimers and larger oligomers linked through their stalk regions, as seen by transmission electron microscopy. Ligation with eptifibatide protected alphaIIb beta3 from SDS-induced subunit dissociation, an effect on electrophoretic mobility not seen with RGD ligands. Despite its distinct cleft, the open conformer resisted guanidine unfolding as effectively as the ligand-free integrin. Thus, we provide the first demonstration that binding a monovalent ligand to alpha Il beta3's extracellular fibrinogen-recognition site stabilizes the receptor's open conformation and enhances self-association through its distant transmembrane and/or cytoplasmic domains. By showing how eptifibatide and RGD peptides, ligands with distinct binding sites, each affects alpha IIb beta3's conformation, our findings provide new mechanistic insights into ligand-linked integrin activation, clustering and signaling.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 00:30:40