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Review
. 2023 Jun 1;435(11):167860.
doi: 10.1016/j.jmb.2022.167860. Epub 2023 Jun 16.

Vital for Viruses: Intrinsically Disordered Proteins

H Jane Dyson  1
Affiliations
Review

Vital for Viruses: Intrinsically Disordered Proteins

H Jane Dyson. J Mol Biol. .

Abstract

Viruses infect all kingdoms of life; their genomes vary from DNA to RNA and in size from 2kB to 1 MB or more. Viruses frequently employ disordered proteins, that is, protein products of virus genes that do not themselves fold into independent three-dimensional structures, but rather, constitute a versatile molecular toolkit to accomplish a range of functions necessary for viral infection, assembly, and proliferation. Interestingly, disordered proteins have been discovered in almost all viruses so far studied, whether the viral genome consists of DNA or RNA, and whatever the configuration of the viral capsid or other outer covering. In this review, I present a wide-ranging set of stories illustrating the range of functions of IDPs in viruses. The field is rapidly expanding, and I have not tried to include everything. What is included is meant to be a survey of the variety of tasks that viruses accomplish using disordered proteins.

Keywords: Protein disorder; post-translational modification; protein–protein interaction; viral oncoproteins; virus proteins.

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Conflict of interest statement

The author declares no conflict of interest

Figures

Figure 1.
Figure 1.
Schematic diagram of the herpes virus structure.
Figure 2.
Figure 2.
Schematic diagram showing regions of the LANA protein of KSHV (adapted from ref.).
Figure 3.
Figure 3.
Schematic diagram of the HPV genome. E1, E2, E4 (orange) are replication and transcription proteins. E5, E6 and E7 (red) are oncoproteins. L1 and L2 (blue) are capsid proteins.
Figure 4.
Figure 4.
Sequence alignment of HPV E7 sequences from several strains. The constant regions CR1, CR2, and CR3 are indicated. The LxCxE interaction motif and the two CxxC zinc-binding motifs are shown boxed.
Figure 5.
Figure 5.
Schematic diagram showing the cell cycle. A. Cell cycle showing phases where cell division, growth and DNA synthesis occur. B. States of pRb during mitosis and first growth phase. Dephosphorylated pRb binds the E2F and DP proteins, arresting the cell cycle at the G2 checkpoint. Cyclin dependent kinases are inhibited by the p21 cyclin dependent kinase inhibitor. C. Receipt of a signal dissociates the CDK-p21 complex, releasing the CDK to phosphorylate pRb, which frees the E2F and DP proteins to allow the cell cycle to proceed into the DNA synthesis phase. Figure adapted from reference with permission.
Figure 6.
Figure 6.
Schematic diagram of the ternary complex of HPV E7 (red) with pRb (blue) and CBP/p300 (green) (adapted from with permission)
Figure 7.
Figure 7.
Domain schematic of E1A, showing the four conserved regions (CR1–4) and the sequence comparison for residues 1–138 for several strains of adenovirus.
Figure 8.
Figure 8.
Structure of E1A with partners. A. Ribbon representation of the lowest-energy structure of TAZ2 (residues 1764–1855 of CBP) in complex with E1A (residues 53–83). Zinc atoms are shown as gray spheres. B. Structural model of the ternary complex of E1A, TAZ2 and pRb, generated using the crystal structure of pRb in complex with E1A (PDB 2R7G), the NMR structure of TAZ2 in complex with E1A (PDB 2KJE), and the crystal structure of the LxCxE region of the HPV E7 peptide (homologous to residues 122–125 of E1A) (PDB 1GUX). The flexible linker between CR1 and CR2 is represented by a dotted line. (Figures adapted from reference with permission).
Figure 9.
Figure 9.
Schematic diagram showing the structural and nonstructural proteins in the Dengue polyprotein. C: capsid; prM: precursor membrane; E: envelope; NS1, 2A, 2B, 3, 4A, 4B, 5: non-structural proteins. Adapted from .
Figure 10.
Figure 10.
Organization and structure of the components of the RNA synthesis machinery in paramyxoviruses. (A) Schematic representation of the viral genome and the regulatory elements. The genome contains at least six conserved adjacent genes separated by intergenic regions (IR). These genes encode for the nucleoprotein (N), the phosphoprotein (P), the matrix protein (M), the fusion protein (F), the receptor-binding protein (RBP) and the large protein (L). The promoters located at the 3’ end of the genome (transcription and replication) and the antigenome (replication only) are bipartite and made of two promoter elements (PE1 and PE2). The transcription of each gene starts on a “gene start” signal (GS, in yellow) and ends on a “gene end” signal (GE, orange). (B) Cartoon representation of the structure of the protein components of the RNA synthesis machinery of parainfluenza virus 5 (PIV5) (N, PDB: 4XJN; PNTD, PDB: 5WKN; POD, PXD, and L, PDB: 6V85). Disordered regions are represented as dotted lines. (C) Schematic representation of viral transcription and replication. Encapsidated genomes are transcribed into a gradient of mRNAs, Replication of the genomes requires the production of encapsidated genome intermediates. Figure reproduced from reference with permission.
Figure 11.
Figure 11.
Dynamics and Interactions of the Nipah virus (NiV) phosphoprotein. A. Schematic representation of the NiV phosphoprotein (P) and nucleoprotein (N). The black lines represent disordered regions, red waved lines represent α-helical molecular recognition elements (α-MoRE) and colored boxes represent structured domains. Green arrows indicate known interactions between N and P. Dotted arrows indicate interactions with imprecisely defined binding sites. Orange arrows show the known interaction sites with L. NTARM = N-terminal arm region of N; NNTD = N-terminal domain of N; NCTD = C-terminal domain of N; CTARM = C-terminal arm region of N; PCM =N0 chaperone module of P; PMD = multimerization domain of P; PXD = X domain of P; PNTR and PCTR = N- and C-terminal regions of P. B. Schematic representation of the conformational equilibrium of PXD and of its interaction with NTAIL. Conformers labeled 2HDim, 2H and 3H co-exist in solution. Crystal structures of PXD alone (PDB 7PON) and in complex with NTAIL (PDB 7PNO) are also shown. Figure adapted from reference with permission.
Figure 12.
Figure 12.
Proposed model of the location of NTAIL in intact nucleocapsids. The three-dimensional coordinates of the RSV N-RNA subunit docked into the EM density map of measles virus N-RNA were used. The conformational sampling algorithm flexible-meccano was used to build chains from the C-terminus of the folded domain of NCORE (successive NCORE monomers are colored green and yellow), allowing prediction of NMR parameters measured in solution. The modeled NTAIL is shown in red, with 13 NTAIL conformers from a single turn of capsid shown. The position of the RNA is shown in blue. Figure adapted from reference with permission.
Figure 13.
Figure 13.
Structure of the KID:cMyb:MLL ternary complex (PDB 2AGH) showing the binding sites on KIX (gray) occupied by the activation domains of c-Myb (blue) and MLL (green).
Figure 14.
Figure 14.
Domain structure of HBZ, showing the amino acid sequence of the disordered activation domain. AD, activation domain; BR1, 2, 3, basic regions; ZIP, leucine zipper. The two sequence motifs, AD1 and AD2, are shown in red.
Figure 15.
Figure 15.
Crystal structure of the ternary complex of KIX (gray), c-Myb (black), and HBZ(3–77) (green). AD1 is shown in yellow and AD2 in blue.
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