VP40

Structure

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. 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. L-domains are thought to mediate their function in budding through their interaction with specific host cellular proteins, such as TSG101 and vps-4.

Function

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.

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.

Significance of VP40

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.

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.

West African 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.

References

References

1. Dessen, Andréa. (2000-08-15). "Crystal structure of the matrix protein VP40 from Ebola virus". The EMBO Journal.
2. (August 2000). "Crystal structure of the matrix protein VP40 from Ebola virus". EMBO J..
3. (February 2003). "Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4". J. Mol. Biol..
4. (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..
5. (2012). "Assembly of Ebola Virus Matrix Protein VP40 Is Regulated by Latch-Like Properties of N and C Terminal Tails.". PLOS ONE.
6. Madara, Jonathan J. (2017-02-05). "The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target". Future Virology.
7. Balmith, Marissa. (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]].