Proteolytic refolding of the HIV‐1 capsid protein amino‐terminus facilitates viral core assembly
Open accessAbstract
After budding, the human immunodeficiency virus (HIV) must 'mature' into an infectious viral particle. Viral maturation requires proteolytic processing of the Gag polyprotein at the matrix-capsid junction, which liberates the capsid (CA) domain to condense from the spherical protein coat of the immature virus into the conical core of the mature virus. We propose that upon proteolysis, the amino-terminal end of the capsid refolds into a beta-hairpin/helix structure that is stabilized by formation of a salt bridge between the processed amino-terminus (Pro1) and a highly conserved aspartate residue (Asp51). The refolded amino-terminus then creates a new CA-CA interface that is essential for assembling the condensed conical core. Consistent with this model, we found that recombinant capsid proteins with as few as four matrix residues fused to their amino-termini formed spheres in vitro, but that removing these residues refolded the capsid amino-terminus and redirected protein assembly from spheres to cylinders. Moreover, point mutations throughout the putative CA-CA interface blocked capsid assembly in vitro, core assembly in vivo and viral infectivity. Disruption of the conserved amino-terminal capsid salt bridge also abolished the infectivity of Moloney murine leukemia viral particles, suggesting that lenti- and oncoviruses mature via analogous pathways.
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A beta-hairpin is formed by the N-terminal residues in mature-like CA, stabilized by a salt bridge between the N-terminal proline and a conserved aspartate in helix 3.
“A beta-hairpin is formed by the N-terminal residues in mature-like CA, stabilized by a salt bridge between the N-terminal proline and a conserved aspartate in helix 3”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [73]
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- Authors
- von Schwedler, U. K., Stemmler, T. L., Klishko, V. Y., Li, S., Albertine, K. H., Davis, D. R., & Sundquist, W. I.
- Affiliations
- University of Utah (US)
- Corresponding author
- Sundquist, Wesley I.
- Venue
- The EMBO Journal
- Published
- 1998-03-16
- Volume
- 17
- Issue
- 6
- Pages
- 1555-1568
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1170503
- OpenAlex
- W2137919235
- Cited by
- 337
- References
- 8
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 12 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 10 · 2013: 15 · 2012: 17
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Update notices
- erratum (2000-05-15)
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ai037524-04, 1s10rr010489-01a1, 5r01ai040333-04)
- National Institute of Allergy and Infectious Diseases (R01 AI37524, R01 AI40333)
- National Center for Research Resources (S10-RR-10489)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- HIV-1 capsid protein, proteolytic processing, Gag protein, protein refolding, beta-hairpin, salt bridges, virus maturation, Moloney murine leukemia virus, viral infectivity
- MeSH terms
- Amino Acid Sequence, Capsid, Cell Line, Humans, Molecular Sequence Data, Moloney murine leukemia virus, Recombinant Fusion Proteins, T-Lymphocytes, Viral Matrix Proteins, Virion, HIV-1, Gene Products, gag, Conserved Sequence, Point Mutation, Protein Structure, Secondary, Protein Folding, Virus Assembly, Nuclear Magnetic Resonance, Biomolecular
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