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

Miguel A. Gonzalez-Lozano, Ernst W. Schmid, Enya Miguel Whelan, Yizhi Jiang, Joao A. Paulo, Johannes C. Walter and J. Wade Harper ()
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Miguel A. Gonzalez-Lozano: Harvard Medical School
Ernst W. Schmid: Harvard Medical School
Enya Miguel Whelan: Harvard Medical School
Yizhi Jiang: Harvard Medical School
Joao A. Paulo: Harvard Medical School
Johannes C. Walter: Harvard Medical School
J. Wade Harper: Harvard Medical School

Nature, 2025, vol. 643, issue 8070, 252-261

Abstract: 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 spectrometry4–7 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.

Date: 2025
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DOI: 10.1038/s41586-025-09059-y

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