Functional and evolutionary analysis of viral proteins containing a Rossmann-like fold

Abstract

Viruses are the most abundant life form and infect practically all organisms. Consequently, these obligate parasites are a major cause of human suffering and economic loss. Rossmann-like fold is the most populated fold among α/β-folds in the Protein Data Bank and proteins containing Rossmann-like fold constitute 22% of all known proteins 3D structures. Thus, analysis of viral proteins containing Rossmann-like domains could provide an understanding of viral biology and evolution as well as could propose possible targets for antiviral therapy. We provide functional and evolutionary analysis of viral proteins containing a Rossmann-like fold found in the evolutionary classification of protein domains (ECOD) database developed in our lab. We identified 81 protein families of bacterial, archeal, and eukaryotic viruses in light of their evolution-based ECOD classification and Pfam taxonomy. We defined their functional significance using enzymatic EC number assignments as well as domain-level family annotations.

Keywords: Rossmann-like fold; evolution; viral proteins.

Figure 1

Amount of proteins groups in different viral families. Green color indicates virus families which parasite on Bacteria, violet—on Archea, orange—on Eukaryote. Red color indicates family groups, blue—homology groups.

Figure 2

(A–L) Topology groups of phages proteins containing minimal Rossmann fold. Structure colored by rainbow. β topology is specified for middle β‐sheet only.

Figure 3

(A–D) Topology groups of Archeal viral proteins containing minimal Rossmann fold. Structure colored by rainbow. β topology is specified for middle β‐sheet only.

Figure 4

Homology groups distribution. Protein homology groups counts from bacteria—(blue bar), archea—(red bar), and eukaryote—(green bar) infecting viruses.

Figure 5

A tree of viral helicases. Structure‐based distances between representative P‐loop domains from ECOD family viral helicases were estimated using DaliZ scores. Nodes of the tree are labeled by PDB and colored according to superfamily. Structures are colored in rainbow according to the core Rossmann‐like topology common to all viral helicase domains. Terminal extentions (white) and insertions (pink) decorate the core fold. Where present, active site molecules are in stick.

Figure 6

Viral methyltransferase (MT) domains. The core MT topology (sheet order 3214576) is colored by α/β units in rainbow from N‐terminus (blue) to C‐terminus (red), with the last antiparallel strand that marks the fold in red. N‐terminal (slate) and C‐terminal (salmon) extensions and insertions (white) to the core MT fold are colored. (A) Slow evolving viral FtsJ family MT from Dengue virus NS5 [4v0r] highlights typical AdoMet (black stick) and cap (magenta stick) binding. (B) Fast evolving Vaccinia virus V39 MT [1v39] retains similar AdoMet binding but diverges in cap binding. (C) Fast evolving inactive Alphavirus P32 MT domain [4gua] has deteriorated around the AdoMet site, yet binds RNA (indicated by SO4 spheres). (D) Duplicated inactive MT domain in transcribing cytoplasmic polyhedrosis virus [3jay] binds AdoMet and alters capsid conformation to ultimately activate (E) functional MT domain. (F) MT‐like domain from SARS virus NSP15 [2h85] has significantly deteriorated AdoMet binding site, yet retains the antiparallel strand (red).

Figure 7

Novel viral Rossmann‐like motifs. Two viral‐specific families retain minimal Rossmann‐like motifs colored in rainbow from N‐terminus (blue) to C‐terminus (red). (A) The N‐terminal domain from IBV Nsp2a [3ld1] has a unique β/α insertion (white) after the first helix forming an antiparallel interaction with strand 2 and an additional C‐terminal helix (salmon). (B) The N‐terminal domain from Flavivirus NS1 includes an N‐terminal helix (slate) and a different insertion (white) in the same position as in IBV Nsp2a, but forming a parallel interaction with strand 2.

Figure 8

Minimal Rossmann fold motifs. (A–C) Examples of minimal Rossmann fold motifs. Secondary structure is colored by rainbow from blue (N‐terminal part) to red (C‐terminal part).