Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements

Abstract

Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular “weaponry” deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, we term them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid-binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.IMPORTANCE This is the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems.

Genome sequencing and assessment of plant growth-promoting properties of a Serratia marcescens strain isolated from vermicompost

“…as conjugative transposons and plasmids to evade restriction by host defense systems (Iyer et al 2017). 249…”

The unexpected provenance of components in eukaryotic nucleotide-excision-repair and kinetoplast DNA-dynamics from bacterial mobile elements

“…In course of that study [8], we also detected significant sequence similarities between the ArdC-N domain and the Trypanosoma Tc-38 (p38) protein. In addition, our searches pointed to a potential evolutionary relationship between ArdC-N and the DNA-binding domains of the nucleotide excision repair (NER) XPC/Rad4 protein [20].…”

“…Thus, they are unceasingly entwined in multilevel conflicts with the host and other co-resident genetic elements, which possesses mechanisms to combat the negative effects of these entities to its own fitness [1-3]. Such inter-genomic and intra-genomic biological conflicts have spawned numerous molecular adaptations that function as “biochemical armaments” in both cellular genomes and the selfish elements: prime examples include restriction-modification [4, 5], toxin-antitoxin [6], CRISPR/Cas [7], and polyvalent protein systems [8] among others. Intriguingly, examination of some of these above-listed prokaryotic conflict systems has also led to the realization that they are potential evolutionary “nurseries” for molecular innovation spurred by the pressures for rapid adaptations.…”

“…The ArdC proteins from the plasmids pSA and RP4 are the founding members of a class of proteins, delivered by plasmids and certain phages into the host cell along with their DNA during invasion, termed “polyvalent proteins”, which at the interface of the biological conflict with their hosts [8, 16]. The ArdC protein has been shown to be an anti-restriction factor in the lncW plasmid pSA [16] and was also shown to bind single-stranded DNA (ssDNA) [16].…”

“…1A). The ArdC-N is one of the most prevalent domains in the polyvalent proteins and is coupled with multiple domains possessing an array of disparate effector activities or other DNA-binding domains [8] (Fig. 1A).…”