Extensive domain shuffling in transcription regulators of DNA viruses and implications for the origin of fungal APSES transcription factors

Abstract

Background: Viral DNA-binding proteins have served as good models to study the biochemistry of transcription regulation and chromatin dynamics. Computational analysis of viral DNA-binding regulatory proteins and identification of their previously undetected homologs encoded by cellular genomes might lead to a better understanding of their function and evolution in both viral and cellular systems.

Results: The phyletic range and the conserved DNA-binding domains of the viral regulatory proteins of the poxvirus D6R/N1R and baculoviral Bro protein families have not been previously defined. Using computational analysis, we show that the amino-terminal module of the D6R/N1R proteins defines a novel, conserved DNA-binding domain (the KilA-N domain) that is found in a wide range of proteins of large bacterial and eukaryotic DNA viruses. The KilA-N domain is suggested to be homologous to the fungal DNA-binding APSES domain. We provide evidence for the KilA-N and APSES domains sharing a common fold with the nucleic acid-binding modules of the LAGLIDADG nucleases and the amino-terminal domains of the tRNA endonuclease. The amino-terminal module of the Bro proteins is another, distinct DNA-binding domain (the Bro-N domain) that is present in proteins whose domain architectures parallel those of the KilA-N domain-containing proteins. A detailed analysis of the KilA-N and Bro-N domains and the associated domains points to extensive domain shuffling and lineage-specific gene family expansion within DNA virus genomes.

Conclusions: We define a large class of novel viral DNA-binding proteins and their cellular homologs and identify their domain architectures. On the basis of phyletic pattern analysis we present evidence for a probable viral origin of the fungus-specific cell-cycle regulatory transcription factors containing the APSES DNA-binding domain. We also demonstrate the extensive role of lineage-specific gene expansion and domain shuffling, within a limited set of approximately 24 domains, in the generation of the diversity of virus-specific regulatory proteins.

Figure 1

Sequence and structural analysis of the KilA-N domain. (a) Multiple alignment of KilA-N and APSES domains. Sequences are designated by their gene name, followed by species abbreviation and the Genbank index (gi) number. Species abbreviations are listed in Materials and methods. The coloring reflects the conservation profile at 80% consensus of amino acids. h, hydrophobic residues (L,I,Y,F,M,W,A,C,V in the single-letter amino-acid code); a,aromatic residues (F,H,Y,W); and l, aliphatic residues (L,I,A,V), all shaded yellow. c, charged residues (K,E,R,D,H); +, basic residues (K,R,H); -, acidic residues (D,E); and p, polar residues (S,T,E,D,R,K,H,N,Q), all colored magenta. s, small residues (S,A,C,G,D,N,P,V,T) colored green. b, big residues (L,I,F,M,W,Y,E,R,K,Q) shaded gray. Further grouping of sequences is based on the association of KilA-Nwith other domains as follows: 1, fused to KilA-C; 2, fused to D3ORF11-C; 3, fused to Mx8p63C; 4, fused to T5ORF172; 5, fused to Bro-C; 6, fused to a CCCH domain and a RING finger; 7, fused to a ring finger. (b) Structural comparison of the APSES, LAGLIDADG and tRNA splicing endonuclease (TEN) domains. The ribbon diagrams were drawn using Molscript.

Figure 2

Domain architectures and architecture graphs of the KilA-N, Bro-N and other associated domains. (a) Domain architectures of the KilA-N, Bro-N and other associated domains. Gene names and species abbreviations are given below the architectures. Species abbreviations are listed in Materials and methods. (b) Domain architecture graph for the KilA-N, Bro-N and other associated domains. Each vertex represents a domain, and edges indicate domain combinations. Arrows point from the amino terminus to the carboxyl terminus of a multidomain protein. Architectures involving more than two colinear domains (see the three-domain proteins in (a)) are connected by red lines. Circular arrows indicate multiple copies of the same domain.

Figure 3

Multiple alignment of Bro-N domains. The color scheme is as in Figure 1. The coloring reflects the conservation profile of amino acid residues at 85% consensus. Further groupings described reflect domain architectures as follows: 1, fused to KilA-C; 2, fused to Mx8P63C; 3, fused to P22AR-C; 4, Xylella fastidiosa specific Bro-N duplications and fusions; 5, fused to T5ORF172; 6, fused to Bro-C; 7, duplicated Bro-N fused to Bro-C; 8, fused to a VSR nuclease; 9, duplicated Bro-N; 10, fused to a HTH. Species abbreviations are listed in Materials and methods.