Summary: The endoplasmic reticulum (ER) membrane protein complex (EMC) is a key contributor to biogenesis and membrane integration of transmembrane proteins, but our understanding of its mechanisms and the range of EMC-dependent proteins remains incomplete. Here, we carried out an unbiased mass spectrometry (MS)-based quantitative proteomic analysis comparing membrane proteins in EMC-deficient cells to wild-type (WT) cells and identified 36 EMC-dependent membrane proteins and 171 EMC-independent membrane proteins. Of these, six EMC-dependent and six EMC-independent proteins were further independently validated. We found that a common feature among EMC-dependent proteins is that they contain transmembrane domains (TMDs) with polar and/or charged residues. Mutagenesis studies demonstrate that EMC dependency can be converted in cells by removing or introducing polar and/or charged residues within TMDs. Our studies expand the list of validated EMC-dependent and EMC-independent proteins and suggest that the EMC is involved in handling TMDs with residues challenging for membrane integration. : The endoplasmic reticulum membrane protein complex (EMC) contributes to the biogenesis of transmembrane proteins. Using mass spectrometry-based quantitative proteomic analysis, Tian et al. identify EMC-dependent and EMC-independent proteins. The authors find evidence that the EMC is involved in handling transmembrane domains with polar and/or charged residues that are challenging for membrane integration. Keywords: mass spectrometry-based proteomics, ER membrane protein complex, membrane protein synthesis, transmembrane domain, polar residue, charged residue, transporter activity, EMC, transmembrane domain, transporter, ion channels
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