Conformational regulation of integrin structure and function

被引:424
作者
Shimaoka, M [1 ]
Takagi, J [1 ]
Springer, TA [1 ]
机构
[1] Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol & Anesthesia, Boston, MA 02115 USA
来源
ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE | 2002年 / 31卷
关键词
I domain; conformational change; affinity regulation; divalent cations; signal transmission;
D O I
10.1146/annurev.biophys.31.101101.140922
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Integrins are a structurally elaborate family of heterodimers that mediate divalent cation-dependent cell adhesion in a wide range of biological contexts. The inserted (1) domain binds ligand in the subset of integrins in which it is present. Its structure has been determined in two alternative conformations, termed open and closed. In striking similarity to signaling G proteins, rearrangement of a Mg2+-binding site is linked to large conformational movements in distant backbone regions. Mutations have been used to stabilize either the closed or open structures. These show that the snapshots of the open conformation seen only in the presence of a ligand or a ligand mimetic represent a high-affinity, ligand-binding conformation, whereas those of the closed conformation correspond to a low-affinity conformation. The C-terminal a-helix. moves 10 A down the side of the domain in the open conformation. Locking in the conformation of the preceding loop is sufficient to increase affinity for ligand 9000-fold. This C-terminal "bell-rope" provides a mechanism for linkage to conformational. movements in other domains. The transition from the closed to open conformation has been implicated in fast (<1 s) regulation of integrin affinity in response to activation signals from inside the cell. Recent integrin structures and functional studies reveal interactions between beta-propeller, I, and I-like domains in the headpiece, and a critical role for integrin EGF domains in the stalk region. These studies suggest that the headpiece of the integrin faces down toward the membrane in the inactive conformation and extends upward in a "switchblade"-like opening motion upon activation. These long-range structural rearrangements of the entire integrin molecule involving multiple interdomain contacts appear closely linked to conformational changes in the I domain, which result in increased affinity and competence for ligand binding.
引用
收藏
页码:485 / 516
页数:40
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