Protein-Protein Interactions in Virus-Host Systems

Abstract

To study virus-host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions-viral-viral or host-host interactions-are constantly targeted and inhibited by exogenous interfaces mediating viral-host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these "hub proteins" evolve. "Party hubs" have multiple interfaces; they establish simultaneous/stable (domain-domain) interactions, and tend to evolve slowly. On the other hand, "date hubs" have few interfaces; they establish transient/weak (domain-motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein-protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus-host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus-host protein interactions.

Keywords: PPI; databases; integrative biology; molecular evolution; protein interaction networks; structural biology; viral evolution; virus-host interactions.

Figure 1

Structure of a DDI between a host domain (V-set domain, blue) and a viral domain (Herpes glycop D domain, red; PDB 3U82). By rotating each protein 90° outwards, the residues located at no more than 4.5 Å away from its partner's surface are colored yellow, indicating the interface residues.

Figure 2

Representation of CCR5 (blue) bound with a Maraviroc molecule (yellow), superposed with the HIV-1 GP120 V3 loop (red), as proposed by Tamamis and Floudas (2014). As depicted, the drug occupies a CCR5 pocket, blocking its interaction with GP120.

Figure 3

Interologs: homologous interactions. (A) Protein-protein interaction (PDB 4MYW) between a human Nectin-1 (blue protein) and a Glycoprotein D encoded by a Human Herpesvirus 2 (gD, red protein). (B) Interaction (PDB 5X5W) between swine Nectin-1 (light cyan protein) and Suid Herpesvirus 1 gD (pink protein). (C) Superposition of the interologs: both PPIs are found in distinct but homologous systems.

Figure 4

A viral PPI interaction derived from HGT. (A) In host protein networks, CDK6 (gray protein) originally establishes interaction with human Cyclin-A/CCNT1 (blue protein, PDB 3MI9). (B) Interestingly, a viral cyclin encoded by HHV-8, probably acquired by HGT (red protein, PDB 1G3N), is also able to establish similar interactions. (C) As both proteins share the same domain (Cyclin_N; PF00134), the structural superposition between the human cyclin (A) and its viral cognate (B) reveals their folding and binding similarities.

Figure 5

Interaction convergence. (A) In physiological conditions the cell surface Ephrin (gray protein) binds its Ephrin type-A receptor 4 (blue protein, PDB 3GXU). (B) However, during infections of the Paramixovirus Hendra henipavirus, the Ephrin interface is also used by the viral Glycoprotein G, which by convergence evolved its binding capacity (red protein, PDB 2VSK). (C) As shown in the superposition, Ephrin type-A receptor 4 and the viral Glycoprotein G can compete for the same interface on the Ephrin surface.

Figure 6

Current scenario of data availability for studying viral protein interactions. The outer ring (purple) shows the number of species-specific whole genomes sequenced so far. Such data provides us valuable information on genetic diversity. The PPI data (green ring) provide binary information about pairs of interacting proteins. Finally, the inner ring (orange) presents the structural data available, which allow the investigation of PPIs at the atomic level. As shown, for some viral families substantial amounts of data are available at all three levels.