Intrinsically disordered proteins of viruses: Involvement in the mechanism of cell regulation and pathogenesis

Mishra, Pushpendra Mani; Verma, Navneet Chandra; Rao, Chethana; Uversky, Vladimir N.; Nandi, Chayan Kanti

doi:10.1016/bs.pmbts.2020.03.001

Cited by 69 publications

(51 citation statements)

References 367 publications

(462 reference statements)

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“…Our findings also parallel not-yet peer-reviewed reports of SARS-CoV-2 N+RNA phase separation ( 52 , 56 – 59 ). These findings, plus recognition that many other viral nucleocapsid proteins possess domains with high predicted disorder ( 60 ), suggest a general role for phase separation in viral genome packaging and virion assembly. We pinpoint the region of SARS-CoV-2 N responsible for RNA-mediated phase separation as a subdomain of the protein’s central IDR, residues 210–246, which is adjacent to the phospho-regulated serine/arginine (S/R)-rich subdomain ( Fig.…”

Section: Discussionmentioning

confidence: 93%

The SARS-CoV-2 Nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Singh

et al. 2020

Preprint

107

230

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The multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80-90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that a centrally located 40 amino acid intrinsically disordered domain drives phase separation of N protein when bound to RNA, with the morphology of the resulting condensates affected by inclusion in the RNA of the putative SARS-CoV-2 packaging signal. The SARS-CoV-2 M protein, normally embedded in the virion membrane with its C-terminus extending into the virion core, independently induces N protein phase separation that is dependent on the N protein's C-terminal dimerization domain and disordered region. Three-component mixtures of N+M+RNA form condensates with mutually exclusive compartments containing N+M or N+RNA, including spherical annular structures in which the M protein coats the outside of an N+RNA condensate. These findings support a model in which phase separation of the N protein with both the viral genomic RNA and the SARS-CoV-2 M protein facilitates RNA packaging and virion assembly.

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Section: Discussionmentioning

confidence: 93%

The SARS-CoV-2 Nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Singh

et al. 2020

Preprint

107

230

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“…Intriguing research suggests that highly disordered RNA chaperones were among the earliest proteins to evolve, with their PrLDs providing solubilization and entropic exclusion effects and the bypassing of energy consuming iterative annealing activities [ 119 , 120 ]. Plant virus movement proteins (MPs) are also disordered and possess a wide range of functions, such as interacting with viral proteins and vRNA to form ribonucleoprotein complexes facilitating cell-to-cell and long-distance movement of the viral genome within the plant body [ 121 , 122 ]. The cysteine-histidine-rich region of cucumber mosaic virus MP contributes to plasmodesmal targeting and Zn 2+ binding and pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Monette

Mouland

2020

Viruses

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Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.

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“…While protein structure has long been a focus of investigation, IDPs/IDPRs of viruses are proposed to have potential as drug targets [ 39 ]. The contributions of intrinsic disorder to viral pathogenesis and related processes should thus be considered, particularly given the complexity of viral infection processes and associated aspects, such as strategies for cellular control and exploitation.…”

Section: Discussionmentioning

confidence: 99%

On the Prevalence and Potential Functionality of an Intrinsic Disorder in the MERS-CoV Proteome

Alshehri

Manee

Alqahtani

et al. 2021

Viruses

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Middle East respiratory syndrome is a severe respiratory illness caused by an infectious coronavirus. This virus is associated with a high mortality rate, but there is as of yet no effective vaccine or antibody available for human immunity/treatment. Drug design relies on understanding the 3D structures of viral proteins; however, arriving at such understanding is difficult for intrinsically disordered proteins, whose disorder-dependent functions are key to the virus’s biology. Disorder is suggested to provide viral proteins with highly flexible structures and diverse functions that are utilized when invading host organisms and adjusting to new habitats. To date, the functional roles of intrinsically disordered proteins in the mechanisms of MERS-CoV pathogenesis, transmission, and treatment remain unclear. In this study, we performed structural analysis to evaluate the abundance of intrinsic disorder in the MERS-CoV proteome and in individual proteins derived from the MERS-CoV genome. Moreover, we detected disordered protein binding regions, namely, molecular recognition features and short linear motifs. Studying disordered proteins/regions in MERS-CoV could contribute to unlocking the complex riddles of viral infection, exploitation strategies, and drug development approaches in the near future by making it possible to target these important (yet challenging) unstructured regions.

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Intrinsically disordered proteins of viruses: Involvement in the mechanism of cell regulation and pathogenesis

Cited by 69 publications

References 367 publications

The SARS-CoV-2 Nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

The SARS-CoV-2 Nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

On the Prevalence and Potential Functionality of an Intrinsic Disorder in the MERS-CoV Proteome

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