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Crystal Structure of Human Cyclophilin A Bound to the Amino-Terminal Domain of HIV-1 Capsid
Open accessAbstract
The HIV-1 capsid protein forms the conical core structure at the center of the mature virion. Capsid also binds the human peptidyl prolyl isomerase, cyclophilin A, thereby packaging the enzyme into the virion. Cyclophilin A subsequently performs an essential function in HIV-1 replication, possibly helping to disassemble the capsid core upon infection. We report the 2.36 A crystal structure of the N-terminal domain of HIV-1 capsid (residues 1-151) in complex with human cyclophilin A. A single exposed capsid loop (residues 85-93) binds in the enzyme's active site, and Pro-90 adopts an unprecedented trans conformation. The structure suggests how cyclophilin A can act as a sequence-specific binding protein and a nonspecific prolyl isomerase. In the crystal lattice, capsid molecules assemble into continuous planar strips. Side by side association of these strips may allow capsid to form the surface of the viral core. Cyclophilin A could then function by weakening the association between capsid strips, thereby promoting disassembly of the viral core.
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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”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [72]
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“(c) HIV-1 CA (green) bound to CypA (molecular surface; gray) (pdb 1AK4 [23]).”
InfluentialRelationship between Human Immunodeficiency Virus Type 1 Gag Multimerization and Membrane Binding
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“In HIV-1, it was proposed, largely on the basis of crystallographic results [3], that structural rearrangement at the N terminus following proteolysis allows formation of a new CA–CA interface, facilitating assembly of the capsid in the maturing virus [ 3 ,4].”
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“identified as the binding site for CypA (17, 31).”
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“His12 and His62 are located on a face that serves as an interface in a symmetrical side-to-side association of two N-terminal domains (Gamble et al., 1996).”
BackgroundMethodActive site remodeling switches HIV specificity of antiretroviral TRIMCyp
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“This region is quite different in FIV CA, which lacks the proline-rich cyclophilin A binding loop present in HIV-1 (10, 53).”
BackgroundHuman Immunodeficiency Virus Type 1 Replication Is Modulated by Host Cyclophilin A Expression Levels
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“Based on genetic and structural data, current models propose that cyclophilin A interferes with contacts between capsid monomers in the virion core (17, 27).”
BackgroundInfluentialVisualization of a missing link in retrovirus capsid assembly
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“CypA perhaps destabilizes the capsid (p24 Gag protein) shell during viral entry and uncoats (6) and/or performs an additional chaperon function, facilitating correct capsid condensation during viral maturation (12).”
BackgroundRequirements for capsid-binding and an effector function in TRIMCyp-mediated restriction of HIV-1
Diaz‐Griffero, F., Vandegraaff, N., Li, Y., Engelman, K. D., Stremlau, M. H., Welikala, S., Si, Z., Engelman, A., & Sodroski, J. (2006) · Virology · doi:10.1016/j.virol.2006.03.023 · Cited by 95
“TRIMCyp has been shown to bind the monomeric HIV-1 p24 capsid protein (Gamble et al., 1996; Luban et al., 1993).”
BackgroundInfluentialSelyutina, A., Persaud, M., Simons, L. M., Bulnes‐Ramos, Á., Buffone, C., Martínez‐López, A., Scoca, V., Nunzio, F. D., Hiatt, J. B., Marson, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.100 · Cited by 90
Passage of the HIV capsid cracks the nuclear pore
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“At last, the resolution of STA was not sufficient to identify the secondary structure of CypA,butthereisampleevidenceintheliteraturethatcytoplasmic HIV-1 capsids are decorated with CypA, 10,11,23,49 and the respective binding site was clearly occupied in our data.”
Characterization of Rous Sarcoma Virus Gag Particles Assembled In Vitro
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“This conclusion is consistent with cryo-EM size measurements of HIV (32) and RSV (R. Kingston, unpublished data).”
BackgroundInfluentialComparative requirements for the restriction of retrovirus infection by TRIM5α and TRIMCyp
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“Cyp A is known to bind a surface-exposed loop on the HIV-1 p24 capsid protein (Gamble et al., 1996; Luban et al., 1993).”
BackgroundA model for cofactor use during HIV-1 reverse transcription and nuclear entry
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“It has been known for some time that cyclophilin A (CypA) plays a role in HIV-1 infection, with CypA binding to an exposed loop on the surface of the CA protein [37].”
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“CA-NTD contains seven α-helices that form an arrow shaped structure (Gamble et al., 1996; Gitti et al., 1996) (Fig.”
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“Interestingly, reverse-charge LEDGF/p75 mutants restored partial infectivity to otherwise non-infectious HIV-1 integrase mutant viruses that harbored complementary reverse charge substitutions in NTD helix 1 [103, 104].”
BackgroundInfluentialByeon, I. L., Hou, G., Han, Y. H., Suiter, C. L., Ahn, J., Jung, J., Byeon, C., Gronenborn, A. M., & Polenova, T. E. (2012) · Journal of the American Chemical Society · doi:10.1021/ja300937v · Cited by 88
The highly polymorphic cyclophilin A-binding loop in HIV-1 capsid modulates viral resistance to MxB
Liu, Z., Pan, Q., Liang, Z., Qiao, W., Cen, S., & Liang, C. (2015) · Retrovirology · doi:10.1186/s12977-014-0129-1 · Cited by 93
“H87 is located in the cyclophilin A (CypA)-binding loop of HIV-1 capsid (Figure 2A) [18].”
Ramalingam, D., Duclair, S., Datta, S. A. K., Ellington, A. D., Rein, A. R., & Prasad, V. R. (2010) · Journal of Virology · doi:10.1128/jvi.02626-09 · Cited by 89
Dynamic allostery governs cyclophilin A–HIV capsid interplay
Lu, M., Hou, G., Zhang, H., Suiter, C. L., Ahn, J., Byeon, I. L., Perilla, J. R., LANGMEAD, C. J., Hung, I., Gor’kov, P. L., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1516920112 · Cited by 91
Cyclophilin, TRIM5, and innate immunity to HIV-1
Sokolskaja, E., & Luban, J. (2006) · Current Opinion in Microbiology · doi:10.1016/j.mib.2006.06.011 · Cited by 88
Yu, X. G., Lichterfeld, M. D., Chetty, S., Williams, K. L., Mui, S. K., Miura, T., Frahm, N., Feeney, M. E., Tang, Y., Pereyra, F., et al. (2006) · Journal of Virology · doi:10.1128/jvi.01580-06 · Cited by 87
“In addition, KF11 spans the boundary of structurally important regions of the p24 capsid (12) and might therefore be particularly susceptible to fitness costs associated with amino acid changes.”
BackgroundStructure, Function, and Interactions of the HIV-1 Capsid Protein
Rossi, E., Meuser, M. E., Cunanan, C. J., & Cocklin, S. (2021) · Life · doi:10.3390/life11020100 · Cited by 111
Systematic Approaches towards the Development of Host-Directed Antiviral Therapeutics
Prussia, A. J., Thepchatri, P., Snyder, J. P., & Plemper, R. K. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12064027 · Cited by 88
“[108–112,114–117] These results suggest that even a combined host factor analysis is at risk of missing key host components required for viral replication.”
BackgroundCyclophilin A Interacts with HIV-1 Vpr and Is Required for Its Functional Expression
Zander, K., Sherman, M. P., Tessmer, U., Bruns, K., Wray, V., Prechtel, A. T., Schubert, E., Henklein, P., Luban, J., Neidleman, J. A., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305414200 · Cited by 84
The NMR solution conformation of unligated human cyclophilin A 1 1Edited by P. E. Wright
Ottiger, M., Zerbe, O., Güntert, P., & Kurt Wüthrich, A. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1220 · Cited by 84
“Ke et al. (1994) CsA X-ray 2RMA Ke et al. (1994) N-Methyl-4-[(E)-2-butenyl]-4,4-dimethylthreonine-cyclosporin X-ray 2RMB Papageorgiou et al. (1994) (4,N-Dimethylnorleucine)-4-cyclosporin X-ray 1CWC Spitzfaden et al. (1994) CsA NMR 3CYS Mikol et al. (1995) (5-Hydroxynorvaline)-2-cyclosporin X-ray 1MIK Zhao & Ke (1996a)…”
Valiente‐Echeverría, F., Melnychuk, L., Vyboh, K., Ajamian, L., Gallouzi, I., Bernard, N. F., & Mouland, A. J. (2014) · Nature Communications · doi:10.1038/ncomms5819 · Cited by 84
Cyclophilin A interacts with diverse lentiviral capsids
Lin, T., & Emerman, M. (2006) · Retrovirology · doi:10.1186/1742-4690-3-70 · Cited by 83
“CypA interacts with HIV-1 by virtue of a direct binding between residues in a loop between the fourth and fifth alpha-helices of the capsid (CA) protein of HIV-1 and the active site of CypA [4-6].”
MethodHIV Type 1 Gag as a Target for Antiviral Therapy
Waheed, A. A., & Freed, E. O. (2011) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2011.0230 · Cited by 84
Identification of Three Major Phosphorylation Sites within HIV-1 Capsid
Cartier, C., Sivard, P., Tranchat, C., Décimo, D., Des̀granges, C., & Boyer, V. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.27.19434 · Cited by 81
Sec24C is an HIV-1 host dependency factor crucial for virus replication
Rebensburg, S. V., Wei, G., Larue, R. C., Lindenberger, J. J., Francis, A. C., Annamalai, A. S., Morrison, J. H., Shkriabai, N., Huang, S., KewalRamani, V. N., et al. (2021) · Nature Microbiology · doi:10.1038/s41564-021-00868-1 · Cited by 79
Forshey, B. M., Shi, J., & Aiken, C. (2004) · Journal of Virology · doi:10.1128/jvi.79.2.869-875.2005 · Cited by 80
“The wedge-shaped, amino-terminal domain (amino acids 1 to 151) contains seven -helices, a -hairpin, a -turn, and a solvent-exposed loop that binds the host cell protein cyclophilin A (CypA) (11, 14, 33).”
BackgroundCyclophilin A: An auxiliary but not necessary cofactor for TRIM5α restriction of HIV-1
Stremlau, M. H., Song, B., Javanbakht, H., Perron, M. J., & Sodroski, J. (2006) · Virology · doi:10.1016/j.virol.2006.03.015 · Cited by 79
“Effects of CA mutations that abolish Cyp A binding on HIV-1 restriction Residues 89 and 90 on the HIV-1 CA make direct contacts with Cyp A (Gamble et al., 1996).”
BackgroundRole of Vif in Stability of the Human Immunodeficiency Virus Type 1 Core
Öhagen, Å., & Gabuzda, D. H. (2000) · Journal of Virology · doi:10.1128/jvi.74.23.11055-11066.2000 · Cited by 79
“Cyclophilin A, a cellular protein that is associated with HIV-1 cores (23, 59), is also an unlikely candidate, since cores of mutant viruses that are deficient for its incorporation into virions are more stable than those of wild-type virus (25, 65).”
BackgroundTian, X., Zhao, C., Zhu, H., She, W., Zhang, J., Liu, J., Li, L., Zheng, S., Wen, Y., & Xie, Y. (2010) · Journal of Virology · doi:10.1128/jvi.02555-09 · Cited by 79
“CypA is incorporated into HIV-1 capsid through direct binding with viral Gag protein (10, 24).”
BackgroundTRIM5α Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation
Chiramel, A. I., Meyerson, N. R., McNally, K. L., Broeckel, R. M., Montoya, V. R., Méndez-Solís, O., Robertson, S. J., Sturdevant, G. L., Lubick, K. J., Nair, V., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.040 · Cited by 78
Genetic Control of Retrovirus Susceptibility in Mammalian Cells
Goff, S. P. (2004) · Annual Review of Genetics · doi:10.1146/annurev.genet.38.072902.094136 · Cited by 78
Eukaryotic cyclophilin as a molecular switch for effector activation
Coaker, G., Zhu, G., Ding, Z., Doren, S. R. V., & Staskawicz, B. J. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05335.x · Cited by 76
“…has been studied extensively in mammalian pathogenesis, initially because of its ability to make direct contact with the HIV-1 capsid proline 90, rendering reverse transcription complexes resistant to antiviral activity in human cells (Luban et al., 1993; Franke et al., 1994; Gamble et al., 1996).”
BackgroundWagner, R., Leschonsky, B., Harrer, E. G., Paulus, C., Weber, C., Walker, B. D., Buchbinder, S., Wolf, H. J., Kalden, J. R., & Harrer, T. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.6.3727 · Cited by 76
Cyclophilins and cyclophilin inhibitors in nidovirus replication
de Wilde, A. H., Pham, U., Posthuma, C. C., & Snijder, E. J. (2018) · Virology · doi:10.1016/j.virol.2018.06.011 · Cited by 76
Retrovirus Capsid Protein Assembly Arrangements
Mayo, K., Huseby, D. L., McDermott, J., Arvidson, B., Finlay, L. A., & Barklis, E. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)01176-2 · Cited by 75
Kong, G., Zhao, Y., Jing, M., Huang, J., Yang, J., Xia, Y., Kong, L., Ye, W., Xiong, Q., Qiao, Y., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005139 · Cited by 74
Selective targeting of ITK blocks multiple steps of HIV replication
Readinger, J. A., Schiralli, G. M., Jiang, J.-K., Thomas, C., August, A., Henderson, A., & Schwartzberg, P. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0709659105 · Cited by 75
“Moreover, ITK may influence other cellular processes that modulate HIV infection in T cells, including protein interactions such as those of Gag with cyclophilin (19), a protein that also interacts with ITK (20).”
BackgroundRegulatory Polymorphisms in the Cyclophilin A Gene, PPIA, Accelerate Progression to AIDS
An, P., Wang, L. H., Hutcheson-Dilks, H., Nelson, G. W., Donfield, S. M., Goedert, J. J., Rinaldo, C. R., Buchbinder, S., Kirk, G. D., O’Brien, S. J., et al. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030088 · Cited by 73
“]. The incorporation of CypA into the HIV-1 virion capsid is mediated through the direct binding between prolyl peptide bond located in a proline-rich loop of the fourth and fifth helices of the HIV-1 capsid and the active sites of CypA [”
BackgroundMattei, S., Tan, A. W. K., Glass, B., Müller, B., Kräusslich, H., & Briggs, J. A. G. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811237115 · Cited by 73
Li, G., & Cui, Q. (2003) · Journal of the American Chemical Society · doi:10.1021/ja0367851 · Cited by 73
Retrovirus maturation-an extraordinary structural transformation
Mattei, S., Schur, F. K., & Briggs, J. A. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.02.008 · Cited by 72
Piotukh, K., Gu, W., Kofler, M., Labudde, D., Helms, V., & Freund, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503405200 · Cited by 72
Virus maturation as a new HIV-1 therapeutic target
Adamson, C. S., Salzwedel, K., & Freed, E. O. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903039714 · Cited by 74
“CANTD and CACTD are separated by a short, flexible interdomain linker (Figure 4A) [28,56,57,99-102].”
BackgroundChatterji, U., Bobardt, M. D., Stanfield, R. L., Ptak, R. G., Pallansch, L. A., Ward, P., Jones, M., Stoddart, C. A., Scalfaro, P., Dumont, J., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506314200 · Cited by 73
Atomic-resolution structure of HIV-1 capsid tubes by magic-angle spinning NMR
Lu, M., Russell, R. W., Bryer, A. J., Quinn, C. M., Hou, G., Zhang, H., Schwieters, C. D., Perilla, J. R., Gronenborn, A. M., & Polenova, T. E. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0489-2 · Cited by 76
Qi, M., Yang, R., & Aiken, C. (2008) · Journal of Virology · doi:10.1128/jvi.01518-08 · Cited by 69
“CypA is specifically incorporated into HIV-1 particles via binding to a flexible loop in the N-terminal domain of CA between helices IV and V (7, 21).”
BackgroundMonaco, S., Berthet-Colominas, C., Novelli, A., Battaı̈, N., Piga, N., Cheynet, V., Mallet, F., & Cusack, S. (2000) · Structure · doi:10.1016/s0969-2126(00)00507-4 · Cited by 71
Metadata
- Authors
- Gamble, T. R., Vajdos, F. F., Yoo, S., Worthylake, D. K., Houseweart, M., Sundquist, W. I., & Hill, C. P.
- Affiliations
- University of Utah (US)
- Corresponding author
- Hill, Christopher P
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1996-12
- Volume
- 87
- Issue
- 7
- Pages
- 1285-1294
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2121753315
- Cited by
- 706
- References
- 59
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 7 · 2023: 18 · 2022: 20 · 2021: 26 · 2020: 16 · 2019: 12 · 2018: 23 · 2017: 21 · 2016: 29 · 2015: 22 · 2014: 25 · 2013: 32 · 2012: 24
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- cyclophilin A, HIV-1 capsid, peptidyl-prolyl isomerase, protein-protein complex, capsid disassembly, viral core, capsid assembly, HIV-1 replication
- MeSH terms
- Amino Acid Isomerases, Capsid, Carrier Proteins, Humans, Models, Molecular, Protein Binding, Virion, HIV-1, Gene Products, gag, Protein Structure, Tertiary, Crystallography, X-Ray, Peptidylprolyl Isomerase
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