Structural basis of laminin binding to the LARGE glycans on dystroglycan.
Structural basis of laminin binding to the LARGE glycans on dystroglycan.
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DOI：
10.1038/nchembio.2146
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发表时间：
2016-10
影响因子：
14.8
通讯作者：
Campbell KP
中科院分区：
文献类型：
--
作者：
Briggs DC;Yoshida-Moriguchi T;Zheng T;Venzke D;Anderson ME;Strazzulli A;Moracci M;Yu L;Hohenester E;Campbell KP
营养不良多糖是一种高度糖基化的细胞外基质受体，在骨骼肌和神经系统中具有重要的功能。受扰糖基化导致的α-DG结合减少是多种肌营养不良症的病理特征。类-乙酰氨基葡萄糖转移酶(LIGH)合成基质结合型杂多糖[-葡萄糖醛酸-β1，3-木糖-α1，3-]n。通过双重外切糖苷酶消化，我们证实该多糖存在于天然的骨骼肌α-DG中。层粘连蛋白α2的层粘连蛋白G样结构域4-5与合成的大分子寡糖结合的高分辨晶体结构揭示了基质结合的原子细节。单一的葡萄糖醛酸-β1，3-木糖二糖重复序列跨越LG4域中的一个钙离子，两个糖中的氧原子取代了钙结合的水分子。螯合结合模式解释了这种蛋白质-碳水化合物相互作用的高亲和力。这些结果揭示了一种新的碳水化合物识别机制，并为阐明肌肉营养不良的机制提供了一个结构框架。
Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose-α1,3-]n. Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle. The atomic details of matrix binding were revealed by a high-resolution crystal structure of laminin G-like (LG) domains 4-5 of laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-β1,3-xylose disaccharide repeat straddles a Ca2+ ion in the LG4 domain, with oxygen atoms from both sugars replacing Ca2+-bound water molecules. The chelating binding mode accounts for the high affinity of this protein-carbohydrate interaction. These results reveal a novel mechanism of carbohydrate recognition and provide a structural framework for elucidating the mechanisms underlying muscular dystrophy.