Cytomegalovirus immediate-early 1 proteins form a structurally distinct protein class with adaptations determining cross-species barriers

Autor: Thomas Stamminger, Sonja Wörz, Yves A. Muller, Franziska Rothemund, Johannes Schweininger, Myriam Scherer, Eva-Maria Schilling
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Cytomegalovirus Infection
Human cytomegalovirus
Intrinsic immunity
Viral Diseases
Protein Folding
viruses
Intranuclear Inclusion Bodies
SUMO protein
Cytomegalovirus
Pathology and Laboratory Medicine
Virus Replication
Biochemistry
Database and Informatics Methods
Medical Conditions
Animal Cells
Medicine and Health Sciences
Macromolecular Structure Analysis
Biology (General)
Peptide sequence
Connective Tissue Cells
Mammals
Crystallography
Physics
Eukaryota
virus diseases
Condensed Matter Physics
Adaptation
Physiological
Cell biology
Infectious Diseases
Lytic cycle
Medical Microbiology
Connective Tissue
Viral Pathogens
Viruses
Vertebrates
Physical Sciences
Cytomegalovirus Infections
Crystal Structure
Human Cytomegalovirus
Pathogens
Cellular Types
Anatomy
Sequence Analysis
Research Article
Primates
Herpesviruses
Protein Structure
Bioinformatics
QH301-705.5
Immunology
Sequence alignment
Biology
Research and Analysis Methods
Microbiology
Immediate-Early Proteins
Species Specificity
Virology
ddc:570
Genetics
medicine
Animals
Solid State Physics
Humans
ddc:610
Microbial Pathogens
Molecular Biology
Biology and life sciences
Organisms
Proteins
Cell Biology
Fibroblasts
biochemical phenomena
metabolism
and nutrition
RC581-607
medicine.disease
Protein tertiary structure
Protein Structure
Tertiary
Rats
Biological Tissue
Viral replication
Amniotes
Parasitology
Immunologic diseases. Allergy
DNA viruses
Sequence Alignment
Zoology
Zdroj: PLoS pathogens 17(8), e1009863-(2021). doi:10.1371/journal.ppat.1009863
PLoS Pathogens, Vol 17, Iss 8, p e1009863 (2021)
PLoS Pathogens
DOI: 10.3204/pubdb-2021-03854
Popis: PLoS pathogens 17(8), e1009863 - (2021). doi:10.1371/journal.ppat.1009863
Restriction factors are potent antiviral proteins that constitute a first line of intracellular defense by blocking viral replication and spread. During co-evolution, however, viruses have developed antagonistic proteins to modulate or degrade the restriction factors of their host. To ensure the success of lytic replication, the herpesvirus human cytomegalovirus (HCMV) expresses the immediate-early protein IE1, which acts as an antagonist of antiviral, subnuclear structures termed PML nuclear bodies (PML-NBs). IE1 interacts directly with PML, the key protein of PML-NBs, through its core domain and disrupts the dot-like multiprotein complexes thereby abrogating the antiviral effects. Here we present the crystal structures of the human and rat cytomegalovirus core domain (IE1CORE). We found that IE1CORE domains, also including the previously characterized IE1CORE of rhesus CMV, form a distinct class of proteins that are characterized by a highly similar and unique tertiary fold and quaternary assembly. This contrasts to a marked amino acid sequence diversity suggesting that strong positive selection evolved a conserved fold, while immune selection pressure may have fostered sequence divergence of IE1. At the same time, we detected specific differences in the helix arrangements of primate versus rodent IE1CORE structures. Functional characterization revealed a conserved mechanism of PML-NB disruption, however, primate and rodent IE1 proteins were only effective in cells of the natural host species but not during cross-species infection. Remarkably, we observed that expression of HCMV IE1 allows rat cytomegalovirus replication in human cells. We conclude that cytomegaloviruses have evolved a distinct protein tertiary structure of IE1 to effectively bind and inactivate an important cellular restriction factor. Furthermore, our data show that the IE1 fold has been adapted to maximize the efficacy of PML targeting in a species-specific manner and support the concept that the PML-NBs-based intrinsic defense constitutes a barrier to cross-species transmission of HCMV.
Published by PLoS, Lawrence, Kan.
Databáze: OpenAIRE
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