scholarly journals Globally defining the effects of mutations in a picornavirus capsid

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Florian Mattenberger ◽  
Victor Latorre ◽  
Omer Tirosh ◽  
Adi Stern ◽  
Ron Geller
Keyword(s):  
Viral Fitness ◽  
Sequence Specificity ◽  
Protein Assemblies ◽  
Multifunctional Protein ◽  
Host Interactions ◽  
Fitness Effects ◽  
Protease Cleavage ◽  
Viral Proteases ◽  
Novel Host ◽  
Protease Cleavage Sites

The capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that play key roles in viral biology and pathogenesis. Despite their importance, a comprehensive understanding of how mutations affect viral fitness across different structural and functional attributes of the capsid is lacking. To address this limitation, we globally define the effects of mutations across the capsid of a human picornavirus. Using this resource, we identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid-encoded motifs. Furthermore, capitalizing on the derived sequence requirements for capsid-encoded protease cleavage sites, we implement a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings represent the most comprehensive investigation of mutational fitness effects in a picornavirus capsid to date and illuminate important aspects of viral biology, evolution, and host interactions.

scholarly journals Globally defining the effects of mutations in a picornavirus capsid

2020 ◽  
Author(s):  
Florian Mattenberger ◽  
Victor Latorre ◽  
Omer Tirosh ◽  
Adi Stern ◽  
Ron Geller
Keyword(s):  
Viral Fitness ◽  
Single Amino Acid ◽  
Sequence Specificity ◽  
Multifunctional Protein ◽  
Humoral Immune ◽  
Fitness Effects ◽  
Humoral Immune Responses ◽  
Novel Host ◽  
Protease Cleavage Sites ◽  
Amino Acid Mutations

ABSTRACTThe capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that protect the viral genome between infection cycles, dictate host and cell tropism, and mediate evasion of humoral immune responses. As such, capsids play key roles in viral biology and pathogenesis. Despite their importance, a comprehensive understanding of how mutations affect viral fitness across different structural and functional attributes of the capsid is lacking. To address this limitation, we globally define the effects of mutations in the capsid of a human picornavirus, generating a comprehensive dataset encompassing >90% of all possible single amino acid mutations. Moreover, we use this information to identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid encoded motifs. Finally, capitalizing on the sequence requirements identified in our dataset for capsid encoded protease cleavage sites, we implement and validate a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings present the most comprehensive investigation of mutational fitness effects in a picornavirus capsid to date and illuminate important aspects of viral biology, evolution, and host interactions.

scholarly journals Running With Scissors: Evolutionary Conflicts Between Viral Proteases and the Host Immune System

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian V. Tsu ◽  
Elizabeth J. Fay ◽  
Katelyn T. Nguyen ◽  
Miles R. Corley ◽  
Bindhu Hosuru ◽  
...  
Keyword(s):  
Immune System ◽  
Gene Evolution ◽  
Evolutionary Constraint ◽  
Host Immune System ◽  
Viral Protease ◽  
Host Interactions ◽  
Cellular Processes ◽  
Protease Cleavage ◽  
Viral Proteases ◽  
Protease Cleavage Sites

Many pathogens encode proteases that serve to antagonize the host immune system. In particular, viruses with a positive-sense single-stranded RNA genome [(+)ssRNA], including picornaviruses, flaviviruses, and coronaviruses, encode proteases that are not only required for processing viral polyproteins into functional units but also manipulate crucial host cellular processes through their proteolytic activity. Because these proteases must cleave numerous polyprotein sites as well as diverse host targets, evolution of these viral proteases is expected to be highly constrained. However, despite this strong evolutionary constraint, mounting evidence suggests that viral proteases such as picornavirus 3C, flavivirus NS3, and coronavirus 3CL, are engaged in molecular ‘arms races’ with their targeted host factors, resulting in host- and virus-specific determinants of protease cleavage. In cases where protease-mediated cleavage results in host immune inactivation, recurrent host gene evolution can result in avoidance of cleavage by viral proteases. In other cases, such as recently described examples in NLRP1 and CARD8, hosts have evolved ‘tripwire’ sequences that mimic protease cleavage sites and activate an immune response upon cleavage. In both cases, host evolution may be responsible for driving viral protease evolution, helping explain why viral proteases and polyprotein sites are divergent among related viruses despite such strong evolutionary constraint. Importantly, these evolutionary conflicts result in diverse protease-host interactions even within closely related host and viral species, thereby contributing to host range, zoonotic potential, and pathogenicity of viral infection. Such examples highlight the importance of examining viral protease-host interactions through an evolutionary lens.

Family-wide characterization of matrix metalloproteinases from Arabidopsis thaliana reveals their distinct proteolytic activity and cleavage site specificity

2013 ◽  
Vol 457 (2) ◽  
pp. 335-346 ◽  
Author(s):  
Giada Marino ◽  
Pitter F. Huesgen ◽  
Ulrich Eckhard ◽  
Christopher M. Overall ◽  
Wolfgang P. Schröder ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Cleavage Site ◽  
Biochemical Properties ◽  
Site Specificity ◽  
Sequence Specificity ◽  
Cleavage Sites ◽  
Protease Cleavage ◽  
Protease Cleavage Sites ◽  
Proteomic Identification

The five recombinant MMP-like proteins of Arabidopsis thaliana have specific biochemical properties. Detailed analysis of their sequence specificity using proteomic identification of protease cleavage sites revealed cleavage profiles similar to human MMPs.

scholarly journals A novel HIV vaccine targeting the protease cleavage sites

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Hongzhao Li ◽  
Robert W. Omange ◽  
Francis A. Plummer ◽  
Ma Luo
Keyword(s):  
Hiv Vaccine ◽  
Cleavage Sites ◽  
Protease Cleavage ◽  
Protease Cleavage Sites

scholarly journals Proteolytic Cleavage of Bovine Adenovirus 3-Encoded pVIII

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Amit Gaba ◽  
Lisanework Ayalew ◽  
Niraj Makadiya ◽  
Suresh Tikoo
Keyword(s):  
Cleavage Site ◽  
Virus Assembly ◽  
Proteolytic Cleavage ◽  
Efficient Production ◽  
Cleavage Sites ◽  
Bovine Adenovirus ◽  
Protease Cleavage Site ◽  
Protease Cleavage ◽  
Protease Cleavage Sites ◽  
Single Protease

ABSTRACT Proteolytic maturation involving cleavage of one nonstructural and six structural precursor proteins including pVIII by adenovirus protease is an important aspect of the adenovirus life cycle. The pVIII encoded by bovine adenovirus 3 (BAdV-3) is a protein of 216 amino acids and contains two potential protease cleavage sites. Here, we report that BAdV-3 pVIII is cleaved by adenovirus protease at both potential consensus protease cleavage sites. Usage of at least one cleavage site appears essential for the production of progeny BAdV-3 virions as glycine-to-alanine mutation of both protease cleavage sites appears lethal for the production of progeny virions. However, mutation of a single protease cleavage site of BAdV-3 pVIII significantly affects the efficient production of infectious progeny virions. Further analysis revealed no significant defect in endosome escape, genome replication, capsid formation, and virus assembly. Interestingly, cleavage of pVIII at both potential cleavage sites appears essential for the production of stable BAdV-3 virions as BAdV-3 expressing pVIII containing a glycine-to-alanine mutation of either of the potential cleavage sites is thermolabile, and this mutation leads to the production of noninfectious virions. IMPORTANCE Here, we demonstrated that the BAdV-3 adenovirus protease cleaves BAdV-3 pVIII at both potential protease cleavage sites. Although cleavage of pVIII at one of the two adenoviral protease cleavage sites is required for the production of progeny virions, the mutation of a single cleavage site of pVIII affects the efficient production of infectious progeny virions. Further analysis indicated that the mutation of a single protease cleavage site (glycine to alanine) of pVIII produces thermolabile virions, which leads to the production of noninfectious virions with disrupted capsids. We thus provide evidence about the requirement of proteolytic cleavage of pVIII for production of infectious progeny virions. We feel that our study has significantly advanced the understanding of the requirement of adenovirus protease cleavage of pVIII.

scholarly journals Identification of the protease cleavage sites in a reconstituted Gag polyprotein of an HERV-K(HML-2) element

Retrovirology ◽  
2011 ◽  
Vol 8 (1) ◽  
pp. 30 ◽  
Author(s):  
Maja George ◽  
Torsten Schwecke ◽  
Nadine Beimforde ◽  
Oliver Hohn ◽  
Claudia Chudak ◽  
...  
Keyword(s):  
Cleavage Sites ◽  
Gag Polyprotein ◽  
Protease Cleavage ◽  
Protease Cleavage Sites

scholarly journals Regulating ENaC’s gate

2020 ◽  
Vol 318 (1) ◽  
pp. C150-C162 ◽  
Author(s):  
Thomas R. Kleyman ◽  
Douglas C. Eaton
Keyword(s):  
Cleavage Sites ◽  
Open Probability ◽  
Protease Cleavage ◽  
Inositol Phospholipids ◽  
Human Disorders ◽  
Protease Cleavage Sites ◽  
Specific Factors ◽  
The Impact ◽  
Channel Transition ◽  
Extracellular Environment

Epithelial Na+ channels (ENaCs) are members of a family of cation channels that function as sensors of the extracellular environment. ENaCs are activated by specific proteases in the biosynthetic pathway and at the cell surface and remove embedded inhibitory tracts, which allows channels to transition to higher open-probability states. Resolved structures of ENaC and an acid-sensing ion channel revealed highly organized extracellular regions. Within the periphery of ENaC subunits are unique domains formed by antiparallel β-strands containing the inhibitory tracts and protease cleavage sites. ENaCs are inhibited by Na+ binding to specific extracellular site(s), which promotes channel transition to a lower open-probability state. Specific inositol phospholipids and channel modification by Cys-palmitoylation enhance channel open probability. How these regulatory factors interact in a concerted manner to influence channel open probability is an important question that has not been resolved. These various factors are reviewed, and the impact of specific factors on human disorders is discussed.

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