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User:Amabotsi/P24 capsid protein

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Introduction

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P24 is the most abundant HIV protein with each virus containing approximately 1,500 to 3,000 p24 molecules.[1] It is the major structural protein within the capsid, and it is involved in maintaining the structural integrity of the virus and facilitating various stages of the viral life cycle, including viral entry into host cells and the release of new virus particles. [2] Detection of p24 protein is used in various diagnostic assays, including antigen tests, to identify the presence of HIV in a person's blood.[3] These tests are designed to detect viral antigens, such as p24, only in the acute phase of HIV infection. After approximately 50 days of infection, the p24 antigen is often cleared from the bloodstream entirely.[4]

Structure

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Structure-of-HIV-1-capsid-A-The-structure-of-the-CA-monomer-showing-the-N and C-terminal domain

P24 has a molecular weight of 24kDa and is encoded by the gag gene. The structure of HIV capsid was formed by X-ray crystallography and cryo-electron microscopy. [5] p24 capsid protein consists of two domains: the N terminal domain and the C-terminal domain connected by flexible inter-domain linkers. The N-terminal domain (NTD) is made up of 7 α-helices (H) and β-hairpin. [6] [7]The C-terminal domain (CTD) has 4 α-helices, and an 11-residue unstructured region. [8][9]. The N-terminal domain (NTD) facilitates contacts within the hexamer, while the C-terminal domain (CTD) forms dimers that bind to adjacent Hexamers.[10] Each hexamer contains a size-selective pore surrounded by six positively charged arginine residues, and the pore is covered by a β-hairpin that can undergo conformational changes, either opening or closing it.[11] Stabilizing the hexamer, an IP6 molecule binds to the pore's center. Additionally, the C-terminal domain includes a Major Homology Region (MHR) spanning amino acids 153 to 172 with 20 highly conserved amino acids.[12] Moreover, the N-terminal domain features a loop (amino acids 85–93) that interacts with cyclophilin A or Cyp A.

Function

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P24 is a structural protein that plays a crucial role in the formation and stability of the viral capsid, which protects the viral RNA. The role of p24 capsid protein can be identified in the different stages of the HIV replication process.

  • Fusion: HIV replication cycle begins when HIV fuses with the surface of the host cell. The capsid containing the virus’s genome and proteins then enters the cells.
  • Reverse transcription: The capsid ensures the secure transport of the viral genome and reverse-transcription machinery from the cytoplasm's periphery to transcriptionally active sites in the nucleus. It achieves this by shielding the viral genome from detection by restriction factors, while still allowing the necessary molecules to diffuse through the core, facilitating the process of reverse transcription.
  • Assembly: It is involved in the assembly of new virus particles, facilitating the proper organization of viral components.
  • Budding: P24 contributes to the viral budding process, ensuring the proper packaging and release of mature and infectious virus particles.

P24 HIV capsid as a therapeutic target

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  • New Antiretroviral therapy

The HIV-1 p24 capsid protein plays crucial roles throughout the viral replication cycle, making it an attractive therapeutic target. Unlike the viral enzymes (protease, reverse transcriptase and integrase) that are currently targeted by small-molecule antiretroviral drugs, p24 capsid proteins operates through protein-protein interactions. Capsid inhibitors, such as Lenacapavir and GS-6207, interfere with the activities of the HIV capsid protein and underwent evaluation in phase-1 clinical trials as monotherapies[13][14]. They demonstrated anti-viral activity against all subtypes with no cross-resistance with current antiretroviral drugs.[13] [14] These findings support therapies aimed at disrupting the functions of the HIV capsid protein.

  • Vaccine design

P24 can induce cellular immune responses and has been included in some vaccine strategies.[15]

See also

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HIV vaccine

Diagnosis

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  • Fourth generation-HIV test

P24 is a target for the immune system, and antibodies against p24 are used in diagnostic tests to detect the presence of HIV antibodies. Fourth-generation HIV immunoassays detect viral p24 protein in the blood (as well as patient antibodies against the virus). Previous generation tests relied on detecting patient antibodies alone; it takes about 3–4 weeks for the earliest antibodies to be detected. The p24 protein can be detected in patient blood as early as 2 weeks after HIV infection, further reducing the window period necessary to accurately detect the HIV status of the patient.[16]

References

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  1. ^ Summers, Michael F.; Henderson, Louis E.; Chance, Mark R.; South, Terri L.; Blake, Paul R.; Perez‐Alvarado, Gabriela; Bess, Julian W.; Sowder, Raymond C.; Arthur, Larry O.; Sagi, Irit; Hare, Dennis R. (1992). "Nucleocapsid zinc fingers detected in retroviruses: EXAFS studies of intact viruses and the solution‐state structure of the nucleocapsid protein from HIV‐1". Protein Science. 1 (5): 563–574. doi:10.1002/pro.5560010502. ISSN 0961-8368. PMC 2142235. PMID 1304355.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ Rossi, Eric; Meuser, Megan E.; Cunanan, Camille J.; Cocklin, Simon (2021). "Structure, Function, and Interactions of the HIV-1 Capsid Protein". Life. 11 (2): 100. doi:10.3390/life11020100. ISSN 2075-1729. PMC 7910843. PMID 33572761.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  3. ^ Gray, Eleanor R.; Bain, Robert; Varsaneux, Olivia; Peeling, Rosanna W.; Stevens, Molly M.; McKendry, Rachel A. (2018-09-24). "p24 revisited: a landscape review of antigen detection for early HIV diagnosis". AIDS. 32 (15): 2089. doi:10.1097/QAD.0000000000001982. ISSN 0269-9370. PMC 6139023. PMID 30102659.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ Hurt, Christopher B.; Nelson, Julie A. E.; Hightow-Weidman, Lisa B.; Miller, William C. (2017). "Selecting an HIV Test: A Narrative Review for Clinicians and Researchers". Sexually Transmitted Diseases. 44 (12): 739. doi:10.1097/OLQ.0000000000000719. ISSN 0148-5717. PMC 5718364. PMID 29140890.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ Zhao, Gongpu; Perilla, Juan R.; Yufenyuy, Ernest L.; Meng, Xin; Chen, Bo; Ning, Jiying; Ahn, Jinwoo; Gronenborn, Angela M.; Schulten, Klaus; Aiken, Christopher; Zhang, Peijun (2013). "Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics". Nature. 497 (7451): 643–646. doi:10.1038/nature12162. ISSN 1476-4687. PMC 3729984. PMID 23719463.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ Gitti, Rossitza K.; Lee, Brian M.; Walker, Jill; Summers, Michael F.; Yoo, Sanghee; Sundquist, Wesley I. (1996-07-12). "Structure of the Amino-Terminal Core Domain of the HIV-1 Capsid Protein". Science. 273 (5272): 231–235. doi:10.1126/science.273.5272.231. ISSN 0036-8075.
  7. ^ Momany, Cory; Kovari, Ladislau C.; Prongay, Andrew J.; Keller, Walter; Gitti, Rossitza K.; Lee, Brian M.; Gorbalenya, Alexander E.; Tong, Liang; McClure, Jan; Ehrlich, Lorna S.; Summers, Michael F.; Carter, Carol; Rossmann, Michael G. (1996). "Crystal structure of dimeric HIV-1 capsid protein". Nature Structural Biology. 3 (9): 763–770. doi:10.1038/nsb0996-763. ISSN 1545-9985.
  8. ^ Du, Shoucheng; Betts, Laurie; Yang, Ruifeng; Shi, Haibin; Concel, Jason; Ahn, Jinwoo; Aiken, Christopher; Zhang, Peijun; Yeh, Joanne I. (2011-02-25). "Structure of the HIV-1 Full-Length Capsid Protein in a Conformationally Trapped Unassembled State Induced by Small-Molecule Binding". Journal of Molecular Biology. 406 (3): 371–386. doi:10.1016/j.jmb.2010.11.027. ISSN 0022-2836. PMC 3194004. PMID 21146540.{{cite journal}}: CS1 maint: PMC format (link)
  9. ^ Gamble, Theresa R.; Yoo, Sanghee; Vajdos, Felix F.; von Schwedler, Uta K.; Worthylake, David K.; Wang, Hui; McCutcheon, John P.; Sundquist, Wesley I.; Hill, Christopher P. (1997-10-31). "Structure of the Carboxyl-Terminal Dimerization Domain of the HIV-1 Capsid Protein". Science. 278 (5339): 849–853. doi:10.1126/science.278.5339.849. ISSN 0036-8075.
  10. ^ Tan, Aaron; Pak, Alexander J.; Morado, Dustin R.; Voth, Gregory A.; Briggs, John A. G. (2021-01-19). "Immature HIV-1 assembles from Gag dimers leaving partial hexamers at lattice edges as potential substrates for proteolytic maturation". Proceedings of the National Academy of Sciences. 118 (3). doi:10.1073/pnas.2020054118. ISSN 0027-8424. PMC 7826355. PMID 33397805.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ Jacques, David A.; McEwan, William A.; Hilditch, Laura; Price, Amanda J.; Towers, Greg J.; James, Leo C. (2016). "HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis". Nature. 536 (7616): 349–353. doi:10.1038/nature19098. ISSN 1476-4687. PMC 4998957. PMID 27509857.{{cite journal}}: CS1 maint: PMC format (link)
  12. ^ Obr, Martin; Kräusslich, Hans-Georg (2018-07-31). "The secrets of the stability of the HIV-1 capsid". eLife. 7: e38895. doi:10.7554/eLife.38895. ISSN 2050-084X. PMC 6067877. PMID 30063007.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  13. ^ a b Link, John O.; Rhee, Martin S.; Tse, Winston C.; Zheng, Jim; Somoza, John R.; Rowe, William; Begley, Rebecca; Chiu, Anna; Mulato, Andrew; Hansen, Derek; Singer, Eric; Tsai, Luong K.; Bam, Rujuta A.; Chou, Chien-Hung; Canales, Eda (2020). "Clinical targeting of HIV capsid protein with a long-acting small molecule". Nature. 584 (7822): 614–618. doi:10.1038/s41586-020-2443-1. ISSN 1476-4687. PMC 8188729. PMID 32612233.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ a b Dvory-Sobol, Hadas; Shaik, Naveed; Callebaut, Christian; Rhee, Martin S. (2022). "Lenacapavir: a first-in-class HIV-1 capsid inhibitor". Current Opinion in HIV and AIDS. 17 (1): 15–21. doi:10.1097/COH.0000000000000713. ISSN 1746-630X.
  15. ^ Larijani, Mona Sadat; Sadat, Seyed Mehdi; Bolhassani, Azam; Pouriayevali, Mohammad Hassan; Bahramali, Golnaz; Ramezani, Amitis. "In Silico Design and Immunologic Evaluation of HIV-1 p24-Nef Fusion Protein to Approach a Therapeutic Vaccine Candidate". Current HIV Research. 16 (5): 322–337. doi:10.2174/1570162x17666190102151717. PMC 6446525. PMID 30605062.{{cite journal}}: CS1 maint: PMC format (link)
  16. ^ "Homepage". UCSF Center for HIV Information. Retrieved 2023-12-07.

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