Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion

	Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion
	Yu, YM; Zhu, JH; Mi, LZ; Walz, T; Sun, H; Chen, JF; Springer, TA
刊名	JOURNAL OF CELL BIOLOGY
	2012
卷号	196 期号:1 页码:131-146
通讯作者	Springer, TA (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Immune Dis Inst, Boston, MA 02115 USA.,springer@idi.harvard.edu
英文摘要	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 alpha(4)beta(7). 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 iondependent adhesion site in alpha(4)beta(7) is essential for binding to MAdCAM-1 in Mg2+ 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.
学科主题	Cell Biology
类目[WOS]	Cell Biology
关键词[WOS]	CRYSTAL-STRUCTURE ; BINDING-SITES ; MONOCLONAL-ANTIBODY ; HUMANIZED ANTIBODY ; ALPHA-4 INTEGRIN ; LIGAND-BINDING ; CROHNS-DISEASE ; HYBRID DOMAIN ; ACTIVATION ; MOLECULE-1
收录类别	SCI
语种	英语
WOS记录号	WOS:000299269000012
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/530]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Yu, YM,Zhu, JH,Mi, LZ,et al. Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion[J]. JOURNAL OF CELL BIOLOGY,2012,196(1):131-146.
APA	Yu, YM.,Zhu, JH.,Mi, LZ.,Walz, T.,Sun, H.,...&Springer, TA.(2012).Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion.JOURNAL OF CELL BIOLOGY,196(1),131-146.
MLA	Yu, YM,et al."Structural specializations of alpha(4)beta(7), an integrin that mediates rolling adhesion".JOURNAL OF CELL BIOLOGY 196.1(2012):131-146.