Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles

Neuman, Benjamin W.

doi:10.1016/j.antiviral.2016.10.005

Cited by 82 publications

(112 citation statements)

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“…Thus, in CoVs, one or two papain-like protease (PL pro ) domain(s) within Nsp3 possess deubiquitinating (DUB) and deISGylating activities (see below; for a recent review on the role of viral proteases in counteracting the host-cell's innate immune system, see Lei and Hilgenfeld (2017)). Interestingly, two ubiquitin-like domains (Ubl1 and Ubl2) exist in all CoVs (see below ;Neuman, 2016). Considering that ubiquitin-like modules are often involved in protein−protein interactions to regulate various biological processes (Hochstrasser, 2009), such as the MHV Ubl1−N interaction mentioned above, a novel possible function of Ub-like domains in CoVs might be the interaction with target proteins of Ub (or ISG15) by mimicking the shape of these two molecules.…”

Section: Ubiquitin-like Domain 1 and The Glu-rich Acidic Regionmentioning

confidence: 99%

“…It comprises residues 113-183 of SARS-CoV Nsp3, with more than 35% Glu and 10% Asp (Serrano et al, 2007). Because of the non-conserved amino-acid sequence, this region is also designated as "hypervariable region (HVR)" (Neuman, 2016). The HVR region is intrinsically disordered in SARS-CoV and in MHV (Serrano et al, 2007;Keane and Giedroc, 2013) and does not affect the conformation of the globular Ubl1 domain in SARS-CoV (Serrano et al, 2007).…”

Section: Ubiquitin-like Domain 1 and The Glu-rich Acidic Regionmentioning

confidence: 99%

“…Two excellent earlier papers dealt with aspects of Nsp3. The first described the state of knowledge of the papain-like protease (PL pro ) (Báez-Santos et al, 2015), while the second adopted a bioinformatics viewpoint when describing Nsp3 and other non-structural proteins involved in anchoring the coronavirus replication/transcription complex (RTC) to modified membranous structures originating from the endoplasmic reticulum (ER) (Neuman, 2016). We build on these fine reviews, focusing on recent results and discussing the structures and functions of the individual Nsp3 domains in sequential order.…”

Section: Introductionmentioning

confidence: 99%

“…It features a somewhat different domain organization in different CoV genera. The individual coronaviruses can possess 10 to 16 domains of which eight domains and two transmembrane regions are conserved, according to a recent bioinformatic analysis (Neuman, 2016). The domain organization of Nsp3 from HCoV NL63 as a representative of alpha-CoVs, and from SARS-CoV in clade B of the genus beta-CoV are displayed in Fig.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

2018

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The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2), the Nsp3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth.

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Section: Ubiquitin-like Domain 1 and The Glu-rich Acidic Regionmentioning

confidence: 99%

Section: Ubiquitin-like Domain 1 and The Glu-rich Acidic Regionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

2018

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“…Belonging to the family Coronaviridae, coronaviruses have one or two viral PL pro (s) and one 3CL pro (M pro ) . The PL pro (s) is (are) part of the nonstructural protein 3 (Nsp3) . PL pro is a cysteine protease with a catalytic triad Cys–His–Asp (Fig.…”

Section: Rna‐virus Proteases Interfering With the Host Innate Immunementioning

confidence: 99%

RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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Enzymes in the time of COVID‐19: An overview about the effects in the human body, enzyme market, and perspectives for new drugs

Fé

Cipolatti

Pinto

et al. 2022

Medicinal Research Reviews

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The rising pandemic caused by a coronavirus, resulted in a scientific quest to discover some effective treatments against its etiologic agent, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). This research represented a significant scientific landmark and resulted in many medical advances. However, efforts to understand the viral mechanism of action and how the human body machinery is subverted during the infection are still ongoing. Herein, we contributed to this field with this compilation of the roles of both viral and human enzymes in the context of SARS‐CoV‐2 infection. In this sense, this overview reports that proteases are vital for the infection to take place: from SARS‐CoV‐2 perspective, the main protease (M pro ) and papain‐like protease (PL pro ) are highlighted; from the human body, angiotensin‐converting enzyme‐2, transmembrane serine protease‐2, and cathepsins (CatB/L) are pointed out. In addition, the influence of the virus on other enzymes is reported as the JAK/STAT pathway and the levels of lipase, enzymes from the cholesterol metabolism pathway, amylase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and glyceraldehyde 3‐phosphate dehydrogenase are also be disturbed in SARS‐CoV‐2 infection. Finally, this paper discusses the importance of detailed enzymatic studies for future treatments against SARS‐CoV‐2, and how some issues related to the syndrome treatment can create opportunities in the biotechnological market of enzymes and the development of new drugs.

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Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles

Cited by 82 publications

References 100 publications

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

RNA‐virus proteases counteracting host innate immunity

Enzymes in the time of COVID‐19: An overview about the effects in the human body, enzyme market, and perspectives for new drugs

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