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In a recent study posted to the bioRxiv* preprint server, researchers explored monkeypox virus (MPXV) proteomics and structural characteristics of the A42R protein, the only MPXV protein in the RCSB PDB (protein data bank) and the only profilin-like protein of poxviruses with known structure.

MPX cases have been increasing across the globe, and an understanding of MPXV structural proteins may improve the development of anti-MPXV drugs. MPXV genomics has been extensively analyzed and reported; however, information on the virus-encoded proteome is limited, especially on the structure of MPXV proteins.

In the present study, researchers described the structure of the MPXV A42R protein.

The team amplified the A42R-encoding open reading frame (ORF) from genomic deoxyribonucleic acid (DNA) of the MPXV Zaire-96-I-16 strain and recombinant A42R was expressed in Escherichia coli and crystallized. A42R structure was analyzed using the single-wavelength anomalous dispersion (SAD) technique and was refined to a resolution of 1.5 Å.

Further, MPXV A42R sequences were aligned with orthopoxvirus profilin-like proteins and human profilin proteins. The A42R protein was overlaid with Homo sapiens profilin 1 (HsPFN1) and PFN2 and electrostatic surface projections of MPXV A42R, HsPFN1, and HsPFN2 were assessed. In addition, mutagenesis analysis was performed and computational models of the A42R protein analogue from ECTV (ectromelia virus) were prepared. Furthermore, MPXV A42R sequences were compared with sequences of other poxvirus profilin-like proteins to determine if understanding the A42R structure would improve the understanding of other poxviruses.

The overlaying of A42R with HsPFN1 and HsPFN2 showed that the proteinaceous structures were aligned with A42R with RMSD (root-mean-square deviation) values of 0.8 Å and 1.0 Å for HsPFN1 and HsPFN2, respectively, with key differences in loop areas. A42R sequences were similar to those of human profilins, although there were structural differences, especially in the loop areas, indicative of weak A42R binding with actin and no binding with poly(L-proline).

Particularly, the fourth loop region of MPSX A42R situated between α2 and β2 was shorter compared to the same area in HsPFN1 and HsPFN2 by four residues (including the Phe59 residue). In human profilins, the fourth loop partially showed helical arrangement (PFN1/PFN2 α3). MPXV A42R structure showed helices (n=3) surrounding seven-stranded β-sheets in comparison to the four helical configurations of other profilins.

The asymmetric A42R unit comprised two chains of polypeptides and chain A remained intact across all (n=133) A42R residues and also comprised one N-terminal alanine residue originating from tobacco-etch mosaic virus (TEV) protease. Chain B comprised 2-133 residues. The seventh loop of MPXV A42R situated between β5 and β6 strains was shorter than HsPFNs by three residues (with Lys90 deletion) and the same region in HsPFN3 was also shorter than that of HsPFN 1 and 2.  The loss/deletions of amino acid (aa) residues weakened the A42R-actin binding.

MPXV ECTV-derived computational model of A42R also estimated that the loops of MPXV profilins would exhibit significant structural differences from those of mammalian profilins. Taken together, the A42R structure showed a seven-stranded β-sheet in an anti-parallel orientation surrounded by α-helices (n=3) and a partial helix. Further, the surface of PIP2 (phosphatidylinositol 4,5-bisphosphate) interactions in the A42R protein of MPXV showed significant electrostatic differences in comparison to that of human profilins with reorganized hydrophobic and basic areas in comparison to HsPFN1 and HsPFN2.

The PFN1 Arg88 residue in HsPFN1 essential for PIP2 binding was substituted by Lys90 and Leu85 residues of HsPFN1 due to aa deletions in the seventh loop of MPXV A42R and the Arg74 residue of HsPFN1 was replaced by a threonine residue (Thr71) in MPXV A42R. The Arg136 residue in PFN1 contributed to an alternate site for PIP2 binding, that corresponded to the Arg129 residue in the A42R protein of MPXV and was conserved across all profilin and profilin-like protein molecules.

Profilins were also bound to cellular proteins and proteins associated with actin via the poly (L-proline) site comprising C- and N-terminal helical regions and the binding was regulated by serine phosphorylation and disrupted by Trp4. In MPXV A42R, the PIP2 surface was dramatically altered by Gly118 and Met114 residues and thus, A42R PIP2 may not bind to microtubules.

The ECTV-derived A42R showed binding with a cellular protein (tropomyosin) that regulates actin-associated protein binding to actin filaments, indicating that actin regulation by profilin-like protein molecules of poxviruses may differ from that by human profilins. MPXV A42R structure was highly preserved across orthopoxviruses with two aa differences from vaccinia virus (VACV) and variola major virus (VARV) and three aa differences from cowpox virus (CPXV).

High sequence similarity/identity was observed between MPXV and distant orthopoxviruses with 100% identity of residues 17-24 forming the β1 strand across nine orthopoxvirus homologs, although there were 39 aa residue differences with nine homologs. Further, arginine residues forming the MPXV arginine patch were conserved across orthopoxviruses, except for the Skunkpox virus (SKPV) protein.

Overall, the study findings highlighted the structural similarities and differences between MPXV A42R and human profilins and showed that A42R could be considered a valid homolog of orthopoxviruses; however, orthopoxvirus replication may not be solely determined by comparing their cellular profilins.

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Actin, Alanine, Amino Acid, Arginine, DNA, Drugs, Genomic, Genomics, Helix, Monkeypox, Phosphorylation, Proline, Protein, Proteome, Proteomics, Serine, Threonine, Tobacco, Vaccinia Virus, Virus, Wavelength

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