Dissection of a retrovirus envelope protein reveals structural similarity to influenza hemagglutinin.
BACKGROUND
The amino-acid sequences of retroviral envelope proteins contain a '4-3 hydrophobic repeat', with hydrophobic amino acids spaced every four and then every three residues, characteristic of sequences that form coiled coils. The 4-3 hydrophobic repeat is located in the transmembrane subunit (TM) of the retroviral envelope protein, adjacent to the fusion peptide, a region that inserts into the host bilayer during the membrane-fusion process. A 4-3 hydrophobic repeat region in an analogous position of the influenza hemagglutinin protein is recruited to extend a three-stranded coiled coil during the conformational change to the fusion-competent state. To determine the conformation of the retroviral TM subunit and the role of the 4-3 hydrophobic repeat, we constructed soluble peptide models of the envelope protein of Moloney murine leukemia virus (MMLV).


RESULTS
The region of the MMLV TM protein external to the lipid envelope (the ectodomain) contains a stably folded, trimeric, protease-resistant core. As predicted, an alpha-helical segment spans the 4-3 repeat. A cysteine-rich region carboxy-terminal to the 4-3 repeat confers a dramatic increase in stability and displays a unique disulfide bonding pattern.


CONCLUSIONS
Our results demonstrate that the MMLV TM subunit can fold into a stable and distinct species in the absence of the receptor-binding 'surface' co-subunit (SU) of the envelope complex. As the SU subunit is readily shed from the surface of the virus, we conclude that the TM subunit structure forms the core of the MMLV membrane-fusion machinery, and that this structure, like the fusion-active conformation of influenza hemagglutinin, contains a three-stranded coiled coil adjacent to the fusion peptide.
Fass
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Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
Kim
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D000595:Amino Acid Sequence; D000818:Animals; D004220:Disulfides; D006389:Hemagglutinins, Viral / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry*; D013438:Sulfhydryl Compounds; D014759:Viral Envelope Proteins / Q000737:chemistry*
D004220:Disulfides; D006389:Hemagglutinins, Viral; D015682:Retroviridae Proteins, Oncogenic; D013438:Sulfhydryl Compounds; D014759:Viral Envelope Proteins; C078678:p15E protein, Murine leukemia virus