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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Xia, Wei Springer, Timothy A. |
| Description | Author Affiliation: Xia W ( Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115); Springer TA ( Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115); |
| Abstract | Integrin $α_{5}β_{1}$ binds to an Arg–Gly–Asp (RGD) motif in its ligand fibronectin. We report high-resolution crystal structures of a four-domain $α_{5}β_{1}$ headpiece fragment, alone or with RGD peptides soaked into crystals, and RGD peptide affinity measurements. The headpiece crystallizes in a closed conformation essentially identical to that seen previously for $α_{5}β_{1}$ complexed with a Fab that allosterically inhibits ligand binding by stabilizing the closed conformation. Soaking experiments show that binding of cyclic RGD peptide with 20-fold higher affinity than a linear RGD peptide induces conformational change in the $β_{1}-subunit$ βI domain to a state that is intermediate between closed (low affinity) and open (high affinity). In contrast, binding of a linear RGD peptide induces no shape shifting. However, linear peptide binding induces shape shifting when $Ca^{2+}$ is depleted during soaking. $Ca^{2+}$ bound to the adjacent to metal ion-dependent adhesion site (ADMIDAS), at the locus of shape shifting, moves and decreases in occupancy, correlating with an increase in affinity for RGD measured when $Ca^{2+}$ is depleted. The results directly demonstrate that $Ca^{2+}$ binding to the ADMIDAS stabilizes integrins in the low-affinity, closed conformation. Comparisons in affinity between four-domain and six-domain headpiece constructs suggest that flexible integrin leg domains contribute to conformational equilibria. High-resolution views of the hybrid domain interface with the plexin–semaphorin–integrin (PSI) domain in different orientations show a ball-and-socket joint with a hybrid domain Arg side chain that rocks in a PSI domain socket lined with carbonyl oxygens. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 50 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Fibronectins Metabolism Integrin Alpha5beta1 Chemistry Models, Molecular Calcium Crystallization Fluorescence Polarization Ligands Peptides, Cyclic Protein Conformation Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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