Structural and Biochemical Analysis of Human Pathogenic Astrovirus Serine Protease at 2.0 Å Resolution

Speroni, Silvia; Rohayem, Jacques; Nenci, S.; Bonivento, Daniele; Robel, Ivonne; Barthel, Julia; Luzhkov, V. B.; Coutard, Bruno; Canard, Bruno; Mattevi, Andrea

doi:10.1016/j.jmb.2009.02.044

Cited by 26 publications

(20 citation statements)

References 47 publications

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“…The crystal structure (2.0 Å resolution) of the predicted protease from a HAstV strain revealed a similarity with viral serine proteases from Sesbania mosaic virus and various picornaviruses (human rhinovirus 2, hepatitis A virus, and foot-and-mouth disease virus). The structural comparison con fi rmed that the catalytic triad is composed of His461, Asp489, and Ser551 [ 63 ] , as was initially proposed using site-directed mutagenesis [ 37 ] .…”

Section: General Features Of Nonstructural Proteinsmentioning

confidence: 74%

Replication Cycle of Astroviruses

Méndez

Murillo

Velázquez

et al. 2012

Astrovirus Research

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Astrovirus infections cause gastroenteritis in mammals and have been identi fi ed as causative agents of diverse pathologies in birds such as hepatitis in ducks and poult enteritis mortality syndrome (PEMS), which causes enteritis and thymic and bursal atrophy in turkeys. Human astroviruses are recognized as the second leading cause of childhood viral gastroenteritis worldwide. Eight traditional astrovirus serotypes have been identi fi ed in humans, but recently novel astrovirus strains isolated from humans have been associated with diseases other than gastroenteritis. Herein we summarize our current knowledge of the astrovirus life cycle. Though there are gaps in our understanding of astrovirus replication, similarities can be drawn from Picornaviridae and Caliciviridae virus families. There are, however, unique characteristics of the astrovirus life cycle, including intracellular proteolytic processing of viral particles by cellular caspases, which has been shown to be required for the maturation and exit of viral progeny.

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Section: General Features Of Nonstructural Proteinsmentioning

confidence: 74%

Replication Cycle of Astroviruses

Méndez

Murillo

Velázquez

et al. 2012

Astrovirus Research

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“…4). The crystal structure of the viral protease has been resolved, showing properties of trypsinlike enzymes with a catalytic Asp-His-Ser triad typical of the serine proteases (74).…”

Section: Translation/replicationmentioning

confidence: 99%

Human Astroviruses

2014

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SUMMARY Human astroviruses (HAtVs) are positive-sense single-stranded RNA viruses that were discovered in 1975. Astroviruses infecting other species, particularly mammalian and avian, were identified and classified into the genera Mamastrovirus and Avastrovirus . Through next-generation sequencing, many new astroviruses infecting different species, including humans, have been described, and the Astroviridae family shows a high diversity and zoonotic potential. Three divergent groups of HAstVs are recognized: the classic ( MAstV 1 ), HAstV-MLB ( MAstV 6 ), and HAstV-VA/HMO ( MAstV 8 and MAstV 9 ) groups. Classic HAstVs contain 8 serotypes and account for 2 to 9% of all acute nonbacterial gastroenteritis in children worldwide. Infections are usually self-limiting but can also spread systemically and cause severe infections in immunocompromised patients. The other groups have also been identified in children with gastroenteritis, but extraintestinal pathologies have been suggested for them as well. Classic HAstVs may be grown in cells, allowing the study of their cell cycle, which is similar to that of caliciviruses. The continuous emergence of new astroviruses with a potential zoonotic transmission highlights the need to gain insights on their biology in order to prevent future health threats. This review focuses on the basic virology, pathogenesis, host response, epidemiology, diagnostic assays, and prevention strategies for HAstVs.

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“…Some of these proteins are in the range of 21 to 27 kDa and include phosphorylated forms (7). The crystal structure of the astrovirus protease has very recently been described (27), suggesting a high preference for Glu and Asp at the P1 substrate position and consequently a preference for the Glu-654/Ile-655 cleavage rather than the Gln-567/Thr-568 cleavage and even suggesting that these latter residues are located in the S1 pocket. However, the inclusion of the coiled-coil domain predicted in the region Thr-568-Glu-654 is of high interest and justifies the construct corresponding to what we call nsP1a/4 protein.…”

Section: Discussionmentioning

confidence: 99%

“…The exact boundaries of these proteins are not well defined. Two cleavage sites yielding the nsP1a/4 have been proposed at positions Gln-567/Thr-568 (14) and Glu-654/ Ile-655 (4,27), which would render products of 40.1 and 30.6 kDa, respectively. With antibodies against a broad region of the nsP1a C terminus, Méndez and colleagues (21) and Willcocks and colleagues (30) reported proteins of 20 kDa and of 34, 20, 6.5, and 5.5 kDa, respectively, but no other cleavage sites were suggested.…”

mentioning

confidence: 99%

“…Previous data from our laboratory with an antibody against a peptide belonging to amino acid positions 778 to 792 of nsP1a revealed proteins of 160 kDa, 75 kDa, 38 to 40 kDa, and 27 to 21 kDa in HAstV-infected CaCo-2 cells (7). The crystal structure of an nsP1a/3-derived protein, whose boundaries are from amino acids 432 to 587, has very recently been resolved (27), suggesting that the cleavage site between nsP1a/3 and nsP1a/4 proteins occurs at Glu-654/Ile-655.…”

mentioning

confidence: 99%

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The C-Terminal nsP1a Protein of Human Astrovirus Is a Phosphoprotein That Interacts with the Viral Polymerase

Fuentes

Guix

Bosch

et al. 2011

J Virol

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Human astrovirus nonstructural C-terminal nsP1a protein (nsP1a/4) colocalizes with the endoplasmic reticulum and viral RNA. It has been suggested that nsP1a/4 protein is involved in the RNA replication process in endoplasmic reticulum-derived intracellular membranes. A hypervariable region (HVR) is contained in the nsP1a/4 protein, and different replicative patterns can be distinguished depending on its variability. In the present work, both the astrovirus RNA-dependent RNA polymerase and four types (IV, V, VI, and XII) of nsP1a/4 proteins have been cloned and expressed in the baculovirus system to analyze their interactions. Different isoforms of each of the nsP1a/4 proteins exist: a nonphosphorylated isoform and different phosphorylated isoforms. While the polymerase accumulates as a monomer, the nsP1a/4 proteins accumulate as oligomers. The oligomerization domain of nsP1a/4-V is mapped between residues 176 and 209. For all studied genotypes, oligomers mainly contain the nonphosphorylated isoform. When RNA polymerase is coexpressed with nsP1a/4 proteins, they interact, likely forming heterodimers. The polymerase binding region has been mapped in the nsP1a/4-V protein between residues 88 and 176. Phosphorylated isoforms of nsP1a/4 type VI show a stronger interactive pattern with the polymerase than the nonphosphorylated isoform. This difference is not observed in genotypes IV and V, suggesting a role of the HVR in modulating the interaction of the nsP1a/4 protein with the polymerase through phosphorylation/dephosphorylation of some critical residues.

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Structural and Biochemical Analysis of Human Pathogenic Astrovirus Serine Protease at 2.0 Å Resolution

Cited by 26 publications

References 47 publications

Replication Cycle of Astroviruses

Replication Cycle of Astroviruses

Human Astroviruses

The C-Terminal nsP1a Protein of Human Astrovirus Is a Phosphoprotein That Interacts with the Viral Polymerase

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