Structure of the PSD-95/MAP1A complex reveals a unique target recognition mode of the MAGUK GK domain.
Structure of the PSD-95/MAP1A complex reveals a unique target recognition mode of the MAGUK GK domain.
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DOI：
10.1042/bcj20170356
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发表时间：
2017-08
期刊：
影响因子：
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通讯作者：
Yitian Xia;Y. Shang;Rong-guang Zhang;Jinwei Zhu
中科院分区：
文献类型：
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作者：
Yitian Xia;Y. Shang;Rong-guang Zhang;Jinwei Zhu
PSD-95家族的膜相关鸟苷酸激酶（MAGUKs）是主要的突触支架蛋白，在树突重塑的动态调节中起关键作用，树突重塑被认为是突触发生和突触可塑性的基础。MAGUK家族蛋白质的鸟苷酸激酶（GK）结构域作为磷肽结合模块起作用。然而，已经发现PSD-95的GK结构域直接结合到神经元特异性微管相关蛋白1A（MAP 1A）的C-末端区域内的肽序列，尽管在原子水平上控制这种磷酸化独立相互作用的详细分子机制缺失。在本研究中，我们确定了PSD-95 GK与MAP 1A肽复合物的晶体结构，分辨率为2.6 μ m。复合物结构表明，与磷-肽/GK复合物中的线性和伸长构象不同，MAP 1A肽采用独特的构象，在一级序列中具有一段彼此远离的疏水残基，并与PSD-95 GK的“疏水位点”和MAP 1A的高度保守的天冬氨酸（D2117）相互作用，其模拟磷酸丝氨酸/天冬氨酸的磷酸化位点。苏氨酸与PSD-95 GK的“磷酸化位点”结合。我们证明，MAP 1A肽可能会经历一个构象转变后，结合PSD-95 GK。已知DLG GK介导的复合物的进一步结构比较揭示了DLG GK的靶识别特异性和多功能性。
The PSD-95 family of membrane-associated guanylate kinases (MAGUKs) are major synaptic scaffold proteins and play crucial roles in the dynamic regulation of dendritic remodelling, which is understood to be the foundation of synaptogenesis and synaptic plasticity. The guanylate kinase (GK) domain of MAGUK family proteins functions as a phosphor-peptide binding module. However, the GK domain of PSD-95 has been found to directly bind to a peptide sequence within the C-terminal region of neuronal-specific microtubule-associated protein 1A (MAP1A), although the detailed molecular mechanism governing this phosphorylation-independent interaction at the atomic level is missing. In the present study, we determine the crystal structure of PSD-95 GK in complex with the MAP1A peptide at 2.6-Å resolution. The complex structure reveals that, unlike a linear and elongated conformation in the phosphor-peptide/GK complexes, the MAP1A peptide adopts a unique conformation with a stretch of hydrophobic residues far from each other in the primary sequence clustering and interacting with the 'hydrophobic site' of PSD-95 GK and a highly conserved aspartic acid of MAP1A (D2117) mimicking the phosphor-serine/threonine in binding to the 'phosphor-site' of PSD-95 GK. We demonstrate that the MAP1A peptide may undergo a conformational transition upon binding to PSD-95 GK. Further structural comparison of known DLG GK-mediated complexes reveals the target recognition specificity and versatility of DLG GKs.