伪V尾3 Integrin Crystal Structures and Their Functional Implications

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• 作者：Xianchi Dong ; Li-Zhi Mi ; Jianghai Zhu ; Wei Wang ; Ping Hu ; Bing-Hao Luo ; Timothy A. Springer
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：November 6, 2012
• 年：2012
• 卷：51
• 期：44
• 页码：8814-8828
• 全文大小：1096K
• 年卷期：v.51,no.44(November 6, 2012)
• ISSN：1520-4995

文摘

Many questions about the significance of structural features of integrin 伪_V尾₃ with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the 伪_V尾₃ ectodomain linked to C-terminal coiled coils (伪_V尾₃-AB) and four transmembrane (TM) residues in each subunit (伪_V尾₃-1TM), respectively. The 伪_V and 尾₃ subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the 尾I domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the 伪_V linker. 伪_V尾₃-AB and 伪_V尾₃-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the 伪_V and 尾₃ subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in 伪_V尾₃-1TM, and differed markedly between 伪_V尾₃-1TM and 伪_V尾₃-AB. Together with the variation in domain鈥揹omain orientation within their bent ectodomains between 伪_V尾₃-AB and 伪_V尾₃-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm.