VP40

From WikiProjectMed
Jump to navigation Jump to search


VP40
VP40 matrix protein hexamer, Ebola virus
Identifiers
SymbolVP40
PfamPF07447
InterProIPR008986
SCOP21h2c / SCOPe / SUPFAM

In molecular biology, VP40 is the name of a viral matrix protein. Most commonly, it is found in the Ebola virus (EBOV),[1] a type of non-segmented, negative-strand RNA virus. Ebola virus causes a severe and often fatal haemorrhagic fever in humans, known as Ebola virus disease. The virus matrix protein VP40 is a major structural protein that plays a central role in virus assembly and budding at the plasma membrane of infected cells. VP40 proteins work by associating with cellular membranes, interacting with the cytoplasmic tails of glycoproteins and binding to the ribonucleoprotein complex.[citation needed]

Structure

VP40 position in the Ebola virus genome

The VP40 monomer consists of two protein domains, the N-terminal oligomerization domain and the C-terminal membrane-binding domain, connected by a flexible linker. Both the N- and C-terminal domains fold into beta sandwich structures of similar topology.[1] Within the N-terminal domain are two overlapping L-domains with the sequences PTAP and PPEY at residues 7 to 13, which are required for efficient budding.[2] L-domains are thought to mediate their function in budding through their interaction with specific host cellular proteins, such as TSG101 and vps-4.[3]

Function

Different structures VP40 assumes in its functional roles

VP40 coordinates numerous functions in the viral life cycle of the Ebola virus. These include: regulation of viral transcription, morphogenesis, packaging and budding of mature virions.[4]

VP40 goes through intermediate states of assembly (e.g. octamers). It has been noted that proteins encoded by EBOV (VP30, VP35, and VP40) act independently as suppressors of RNA silencing, indicating that the virus actively resists cellular RNAi during replication.[4]

Significance of VP40 research

Detail of step-by-step approach used to identify anti-VP40 compounds[5][6]

Study of the matrix protein VP40 is important due to the high mortality rate of the Ebola virus, which is listed as a WHO Risk Group 4 Pathogen, an HHS Select Agent, an NIH/NIAID Category A Priority Pathogen, a CDC Category A Bioterrorism Agent, and a Biological Agent for Export Control by the Australia Group.[4]

Expression of the matrix protein VP40 is sufficient to generate virus-like particles (no viral genetic material) in a mammalian host that are remarkably indistinguishable from live virus, from a morphological standpoint.[4]

Ebola virus outbreak

During and after the 2014-2016 West African Ebola virus epidemic treatment options were sought; among them were the VP40 matrix protein as a target for possible research that may (or may not) lead to a therapeutic option.[7][8]

References

  1. 1.0 1.1 Dessen A, Volchkov V, Dolnik O, Klenk HD, Weissenhorn W (August 2000). "Crystal structure of the matrix protein VP40 from Ebola virus". EMBO J. 19 (16): 4228–36. doi:10.1093/emboj/19.16.4228. PMC 302032. PMID 10944105.
  2. Timmins J, Schoehn G, Ricard-Blum S, Scianimanico S, Vernet T, Ruigrok RW, Weissenhorn W (February 2003). "Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4". J. Mol. Biol. 326 (2): 493–502. doi:10.1016/S0022-2836(02)01406-7. PMID 12559917.
  3. Licata JM, Simpson-Holley M, Wright NT, Han Z, Paragas J, Harty RN (February 2003). "Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4". J. Virol. 77 (3): 1812–9. doi:10.1128/jvi.77.3.1812-1819.2003. PMC 140960. PMID 12525615.
  4. 4.0 4.1 4.2 4.3 Silva LP, Vanzile M, Bavari S, Aman JM, Schriemer DC (2012). "Assembly of Ebola Virus Matrix Protein VP40 Is Regulated by Latch-Like Properties of N and C Terminal Tails". PLOS ONE. 7 (7): e39978. Bibcode:2012PLoSO...739978S. doi:10.1371/journal.pone.0039978. PMC 3390324. PMID 22792204.
  5. Broni, Emmanuel; Ashley, Carolyn; Adams, Joseph; Manu, Hammond; Aikins, Ebenezer; Okom, Mary; Miller, Whelton A.; Wilson, Michael D.; Kwofie, Samuel K. (January 2023). "Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors". International Journal of Molecular Sciences. 24 (7): 6298. doi:10.3390/ijms24076298. ISSN 1422-0067.
  6. Liu, Ching-Hsuan; Hu, Yee-Tung; Wong, Shu Hui; Lin, Liang-Tzung (11 March 2022). "Therapeutic Strategies against Ebola Virus Infection". Viruses. 14 (3): 579. doi:10.3390/v14030579. ISSN 1999-4915.
  7. Madara, Jonathan J; Han, Ziying; Ruthel, Gordon; Freedman, Bruce D; Harty, Ronald N (2017-02-05). "The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target". Future Virology. 10 (5): 537–546. doi:10.2217/fvl.15.6. ISSN 1746-0794. PMC 4480923. PMID 26120351.
  8. Balmith, Marissa; Soliman, Mahmoud E. S. (2017-02-01). "VP40 of the Ebola Virus as a Target for EboV Therapy: Comprehensive Conformational and Inhibitor Binding Landscape from Accelerated Molecular Dynamics". Cell Biochemistry and Biophysics. 75 (1): 65–78. doi:10.1007/s12013-017-0783-8. ISSN 1559-0283. PMID 28144904. S2CID 26535324.subscription needed
This article incorporates text from the public domain Pfam and InterPro: IPR008986