7RU6

Cryo-EM structure of the HIV-1 restriction factor human SERINC3

Summary for 7RU6

• Entry DOI: 10.2210/pdb7ru6/pdb
• EMDB information: 24698 24705
• Descriptor: Serine incorporator 3, SiA (2 entities in total)
• Functional Keywords: flippase, viral restriction, hiv-1, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 80679.14

Authors

Purdy, M.D.,Leonhardt, S.A.,Yeager, M. (deposition date: 2021-08-16, release date: 2022-08-24, Last modification date: 2023-09-06)

Primary citation

Leonhardt, S.A.,Purdy, M.D.,Grover, J.R.,Yang, Z.,Poulos, S.,McIntire, W.E.,Tatham, E.A.,Erramilli, S.K.,Nosol, K.,Lai, K.K.,Ding, S.,Lu, M.,Uchil, P.D.,Finzi, A.,Rein, A.,Kossiakoff, A.A.,Mothes, W.,Yeager, M.
Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry.
Nat Commun, 14:4368-4368, 2023

PubMed Abstract: The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, "crossmember" helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity.

PubMed: 37474505
DOI: 10.1038/s41467-023-39262-2

Experimental method

ELECTRON MICROSCOPY (4.4 Å)