Structural specializations of \(\alpha_4 \beta_7\), an integrin that mediates rolling adhesion

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Structural specializations of \(\alpha_4 \beta_7\), an integrin that mediates rolling adhesion

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Title: Structural specializations of \(\alpha_4 \beta_7\), an integrin that mediates rolling adhesion
Author: Chen, JianFeng; Yu, Yamei; Zhu, Jianghai; Mi, Li-Zhi; Walz, Thomas; Sun, Hao; Springer, Timothy A.

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Citation: Yu, Yamei, Jianghai Zhu, Li-Zhi Mi, Thomas Walz, Hao Sun, JianFeng Chen, and Timothy A. Springer. 2012. Structural specializations of \(\alpha_4 \beta_7\), an integrin that mediates rolling adhesion. The Journal of Cell Biology 196(1): 131-146.
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Abstract: The lymphocyte homing receptor integrin \(\alpha_4 \beta_7\) is unusual for its ability to mediate both rolling and firm adhesion. \(\alpha_4 \beta_1\) and \(\alpha_4 \beta_7\) are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the \(\alpha_4 -\beta_7\)interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in \(\alpha_4\) ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in \(\alpha_4 \beta_7\) is essential for binding to MAdCAM-1 in \(Mg^{2+}\) yet swings away when RO0505376 binds. A novel intermediate conformation of the \(\alpha_4 \beta_7\) headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled.
Published Version: doi:10.1083/jcb.201110023
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255974/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10445609
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