美国哈佛医学院J. Wade Harper研究小组取得一项新突破。他们研究出EndoMAPV1绘制了人类早期核内体复合物的结构景观图。相关论文于2025年5月28日发表在《自然》杂志上。

该课题组人员将纯化早期核内体的交联和天然凝胶质谱与AlphaFold和计算分析相结合，创建了一个系统的人核内体结构相互作用组。课题组人员提出了229个内体蛋白对的结构模型和额外的高阶组装，这些结构模型由实验交联从它们的原生亚细胞环境中支持，表明了先前报道的调节过程的结构机制。利用诱导神经元，研究人员验证了两个候选复合物，它们的相互作用得到交联和结构预测的支持：TMEM230是ATP8和ATP11脂质翻转的亚基，TMEM9和TMEM9B是氯质子反转运蛋白CLCN3、CLCN4和CLCN5的亚基。这种阻力及其伴随的结构网络查看器为理解细胞器结构相互作用组和结构预测的大规模验证提供了一个实验框架。

据介绍，早期或分选内体是动态的细胞器，在蛋白质组控制中发挥关键作用，通过筛选质膜蛋白在溶酶体中回收或降解。这些事件是由许多瞬时相关的调节复合物和整体膜组分协调的，这些成分有助于内核体成熟过程中的细胞器身份。虽然在生化和/或结构水平上研究了已知与内体相关的几百种蛋白质成分和货物中的一部分，但许多内体成分的相互作用伙伴和高阶分子组装仍然未知。

附：英文原文

Title: EndoMAP.v1 charts the structural landscape of human early endosome complexes

Author: Gonzalez-Lozano, Miguel A., Schmid, Ernst W., Miguel Whelan, Enya, Jiang, Yizhi, Paulo, Joao A., Walter, Johannes C., Harper, J. Wade

Issue&Volume: 2025-05-28

Abstract: Early or sorting endosomes are dynamic organelles that play key roles in proteome control by triaging plasma membrane proteins for either recycling or degradation in the lysosome1,2. These events are coordinated by numerous transiently associated regulatory complexes and integral membrane components that contribute to organelle identity during endosome maturation3. Although a subset of the several hundred protein components and cargoes known to associate with endosomes have been studied at the biochemical and/or structural level, interaction partners and higher-order molecular assemblies for many endosomal components remain unknown. Here, we combine crosslinking and native gel mass spectrometry4,5,6,7 of purified early endosomes with AlphaFold8,9 and computational analysis to create a systematic human endosomal structural interactome. We present 229 structural models for endosomal protein pairs and additional higher-order assemblies supported by experimental crosslinks from their native subcellular context, suggesting structural mechanisms for previously reported regulatory processes. Using induced neurons, we validate two candidate complexes whose interactions are supported by crosslinks and structural predictions: TMEM230 as a subunit of ATP8 and ATP11 lipid flippases10 and TMEM9 and TMEM9B as subunits of the chloride–proton antiporters CLCN3, CLCN4 and CLCN5 (ref.11). This resource and its accompanying structural network viewer provide an experimental framework for understanding organellar structural interactomes and large-scale validation of structural predictions.

DOI: 10.1038/s41586-025-09059-y

Source: https://www.nature.com/articles/s41586-025-09059-y