Affinity-MS ERAD-network mapping that first identified the EMC (including TMEM85/EMC4) in human cells and localized it to the ER membrane.

EMC is a transmembrane domain insertase that post-translationally inserts tail-anchored membrane proteins with moderately hydrophobic TMDs.

The EMC engages multipass membrane protein clients cotranslationally, with a particular enrichment for transporters, to enable their biogenesis.

The EMC sets the N-exo topology of the first TMD of GPCRs and other multipass proteins, initiating accurate topogenesis in cooperation with Sec61.

TMEM85/EMC4 interacts with GLUT9/SLC2A9, but ITM2B (not TMEM85) inhibited GLUT9-mediated urate uptake.

Cryo-EM structure of the human EMC; substrate insertion occurs via an enclosed hydrophilic vestibule formed by EMC3 and EMC6, with EMC4 resolved as a membrane subunit of the complex.

Improved cryo-EM model of human EMC assigns three transmembrane domains to EMC4; EMC4/EMC7/EMC10 TMDs partially enclose the hydrophilic insertase vestibule, and substrate photocrosslinking/disulfide crosslinking detects contacts with EMC4 as well as EMC3.

Cryo-EM of an EMC-bound CaV1.2 assembly intermediate shows the EMC acts as a holdase/chaperone during voltage-gated calcium channel assembly; EMC4 participates in the client-engaging cytoplasmic chaperone module and in a lumenal EMC1/EMC4/EMC7/EMC10 subassembly.

Cryo-EM structures of human EMC in apo and VDAC-bound states; EMC4 forms an ordered three-TMH bundle adjacent to the EMC3/EMC6 core that constitutes a sidewall of the hydrophilic vestibule, and the EMC engages VDAC at mitochondria-ER contact sites.

Reconstitution and coarse-grained MD indicate lipid scrambling is a general feature of protein insertases, with EMC scrambling activity localized to EMC3 and EMC4; scrambling occurs in the same hydrophilic channel used for protein insertion.

EMC4 is a proviral host factor for dengue, yellow fever, and Zika viruses, acting both at an early entry/uncoating step and in biogenesis of viral multipass membrane proteins; EMC4 knockout/knockdown strongly reduces infectivity and viral titers.

The EMC promotes biogenesis of flavivirus non-structural multipass transmembrane proteins (e.g., NS4B); EMC associates with these viral clients, consistent with a direct role in viral membrane-protein biogenesis.

EMC4 and EMC7 promote late endosome-to-ER targeting of polyomavirus SV40 during entry; EMC4 engages Rab7 and syntaxin18 and is proposed to act as a tether stabilizing late endosome-ER contacts, with EMC4-FLAG rescue supporting specificity.

Small polytopic ER membrane accessory subunit of the EMC (TMEM85); structural/scaffold subunit, not part of the EMC3/EMC6 catalytic vestibule; interacts with the EMC client transporter GLUT9/SLC2A9.