Qu A, Leahy D J
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Structure. 1996 Aug 15;4(8):931-42. doi: 10.1016/s0969-2126(96)00100-1.
The integrin family of cell-surface receptors mediates a wide variety of cell-cell and cell-extracellular matrix interactions. Integrin-ligand interactions are invariably dependent on the presence of divalent cations, and a subset of integrins contain a approximately 200 amino acid inserted (I) domain that is important for ligand binding activity and contains a single divalent cation binding site. Many integrins are believed to respond to stimuli by undergoing a conformational change that increases their affinity for ligand, and there is a clear difference between two crystal structures of the CD11b I domain with different divalent cations (magnesium and manganese) bound. In addition to the different bound cation, a 'ligand mimetic' crystal lattice interaction in the CD11b I domain structure with bound magnesium has led to the interpretation that the different CD11b I domain structures represent different affinity states of I domains. The influence of the bound cation on I domain structure and function remains incompletely understood, however. The crystal structure of the CD11a I domain bound to manganese is known. We therefore set out to determine whether this structure changes when the metal ion is altered or removed.
We report here the crystal structures of the CD11a I domain determined in the absence of bound metal ion and with bound magnesium ion. No major structural rearrangements are observed in the metal-binding site of the CD11a I domain in the absence or presence of bound manganese ion. The structures of the CD11a I domain with magnesium or manganese bound are extremely similar.
The conformation of the CD11a I domain is not altered by changes in metal ion binding. The cation-dependence of ligand binding thus indicates that the metal ion is either involved in direct interaction with ligand or required to promote a favorable quaternary arrangement of the integrin.
细胞表面受体的整合素家族介导多种细胞间和细胞与细胞外基质的相互作用。整合素-配体相互作用总是依赖于二价阳离子的存在，并且一部分整合素含有一个约200个氨基酸的插入（I）结构域，该结构域对于配体结合活性很重要，并且包含一个单一的二价阳离子结合位点。许多整合素被认为通过发生构象变化来响应刺激，这种构象变化会增加它们对配体的亲和力，并且结合不同二价阳离子（镁和锰）的CD11b I结构域的两种晶体结构之间存在明显差异。除了结合的阳离子不同之外，结合镁的CD11b I结构域结构中的“配体模拟”晶格相互作用导致了这样的解释，即不同的CD11b I结构域结构代表I结构域的不同亲和力状态。然而，结合的阳离子对I结构域结构和功能的影响仍未完全理解。已知结合锰的CD11a I结构域的晶体结构。因此，我们着手确定当金属离子改变或去除时该结构是否会发生变化。
我们在此报告在没有结合金属离子和结合镁离子的情况下测定的CD11a I结构域的晶体结构。在不存在或存在结合锰离子的情况下，在CD11a I结构域的金属结合位点中未观察到主要的结构重排。结合镁或锰的CD11a I结构域的结构极其相似。
CD11a I结构域的构象不会因金属离子结合的变化而改变。因此，配体结合对阳离子的依赖性表明金属离子要么参与与配体的直接相互作用，要么是促进整合素形成有利四级排列所必需的。
