Amino Acid Residues in the Carboxy-Terminal Region of Cottontail Rabbit Papillomavirus E6 Influence Spontaneous Regression of Cutaneous Papillomas

ABSTRACT Previous studies have identified two different strains of cottontail rabbit papillomavirus (CRPV) that differ by approximately 5% in base pair sequence and that perform quite differently when used to challenge New Zealand White (NZW) rabbit skin. One strain caused persistent lesions (progressor strain), and the other induced papillomas that spontaneously regressed (regressor strain) at high frequencies (J. Salmon, M. Nonnenmacher, S. Caze, P. Flamant, O. Croissant, G. Orth, and F. Breitburd, J. Virol. 74:10766-10777, 2000; J. Salmon, N. Ramoz, P. Cassonnet, G. Orth, and F. Breitburd, Virology 235:228-234, 1997). We generated a panel of CRPV genomes that contained chimeric and mutant progressor and regressor strain E6 genes and assessed the outcome upon infection of both outbred and EIII/JC inbred NZW rabbits. The carboxy-terminal 77-amino-acid region of the regressor CRPV strain E6, which contained 15 amino acid residues that are different from those of the equivalent region of the persistent CRPV strain E6, played a dominant role in the conversion of the persistent CRPV strain to one showing high rates of spontaneous regressions. In addition, a single amino acid change (G252E) in the E6 protein of the CRPV progressor strain led to high frequencies of spontaneous regressions in inbred rabbits. These observations imply that small changes in the amino acid sequences of papillomavirus proteins can dramatically impact the outcome of natural host immune responses to these viral infections. The data imply that intrastrain differences between separate isolates of a single papillomavirus type (such as human papillomavirus type 16) may contribute to a collective variability in host immune responses in outbred human populations.

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Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential

Journal of Virology ◽

10.1128/jvi.01248-18 ◽

2018 ◽

Vol 92 (23) ◽

Cited By ~ 11

Author(s):

Nurshariza Abdullah ◽

James T. Kelly ◽

Stephen C. Graham ◽

Jamie Birch ◽

Daniel Gonçalves-Carneiro ◽

...

Keyword(s):

Amino Acid ◽

Measles Virus ◽

Small Ruminant ◽

Significant Proportion ◽

Single Amino Acid ◽

Close Relative ◽

Ecological Niches ◽

Human Populations ◽

Zoonotic Potential ◽

Single Amino Acid Change

ABSTRACTMorbilliviruses infect a broad range of mammalian hosts, including ruminants, carnivores, and humans. The recent eradication of rinderpest virus (RPV) and the active campaigns for eradication of the human-specific measles virus (MeV) have raised significant concerns that the remaining morbilliviruses may emerge in so-called vacated ecological niches. Seeking to assess the zoonotic potential of nonhuman morbilliviruses within human populations, we found that peste des petits ruminants virus (PPRV)—the small-ruminant morbillivirus—is restricted at the point of entry into human cells due to deficient interactions with human SLAMF1—the immune cell receptor for morbilliviruses. Using a structure-guided approach, we characterized a single amino acid change, mapping to the receptor-binding domain in the PPRV hemagglutinin (H) protein, which overcomes this restriction. The same mutation allowed escape from some cross-protective, human patient, anti-MeV antibodies, raising concerns that PPRV is a pathogen with zoonotic potential. Analysis of natural variation within human and ovine SLAMF1 also identified polymorphisms that could correlate with disease resistance. Finally, the mechanistic nature of the PPRV restriction was also investigated, identifying charge incompatibility and steric hindrance between PPRV H and human SLAMF1 proteins. Importantly, this research was performed entirely using surrogate virus entry assays, negating the requirement forin situderivation of a human-tropic PPRV and illustrating alternative strategies for identifying gain-of-function mutations in viral pathogens.IMPORTANCEA significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of the emergence of these viruses, it is necessary to develop a better understanding of what determines virus host range, often at the genetic and structural levels. In this study, we demonstrated that the small-ruminant morbillivirus, a close relative of measles, is unable to use human receptors to enter cells; however, a change of a single amino acid in the virus is sufficient to overcome this restriction. This information will be important for monitoring this virus’s evolution in the field. Of note, this study was undertakenin vitro, without generation of a fully infectious virus with this phenotype.

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Structural and functional analyses of Saccharomyces cerevisiae wild-type and mutant RNA1 genes.

Molecular and Cellular Biology ◽

10.1128/mcb.9.7.2989 ◽

1989 ◽

Vol 9 (7) ◽

pp. 2989-2999 ◽

Cited By ~ 36

Author(s):

H M Traglia ◽

N S Atkinson ◽

A K Hopper

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Open Reading Frame ◽

Single Amino Acid ◽

Temperature Sensitive ◽

Wild Type ◽

Reading Frame ◽

Genomic Deletions ◽

Single Amino Acid Change ◽

Carboxy Terminal

The yeast gene RNA1 has been defined by the thermosensitive rna1-1 lesion. This lesion interferes with the processing and production of all major classes of RNA. Each class of RNA is affected at a distinct and presumably unrelated step. Furthermore, RNA does not appear to exit the nucleus. To investigate how the RNA1 gene product can pleiotropically affect disparate processes, we undertook a structural analysis of wild-type and mutant RNA1 genes. The wild-type gene was found to contain a 407-amino-acid open reading frame that encodes a hydrophilic protein. No clue regarding the function of the RNA1 protein was obtained by searching banks for similarity to other known gene products. Surprisingly, the rna1-1 lesion was found to code for two amino acid differences from wild type. We found that neither single-amino-acid change alone resulted in temperature sensitivity. The carboxy-terminal region of the RNA1 open reading frame contains a highly acidic domain extending from amino acids 334 to 400. We generated genomic deletions that removed C-terminal regions of this protein. Deletion of amino acids 397 to 407 did not appear to affect cell growth. Removal of amino acids 359 to 397, a region containing 24 acidic residues, caused temperature-sensitive growth. This allele, rna1-delta 359-397, defines a second conditional lesion of the RNA1 locus. We found that strains possessing the rna1-delta 359-397 allele did not show thermosensitive defects in pre-rRNA or pre-tRNA processing. Removal of amino acids 330 to 407 resulted in loss of viability.

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A single amino acid switch converts the Sleeping Beauty transposase into an efficient unidirectional excisionase with utility in stem cell reprogramming

Nucleic Acids Research ◽

10.1093/nar/gkz1119 ◽

2019 ◽

Vol 48 (1) ◽

pp. 316-331 ◽

Cited By ~ 4

Author(s):

Lisa Kesselring ◽

Csaba Miskey ◽

Cecilia Zuliani ◽

Irma Querques ◽

Vladimir Kapitonov ◽

...

Keyword(s):

Amino Acid ◽

Signal Sequence ◽

Phylogenetic Analyses ◽

Sleeping Beauty ◽

Single Amino Acid ◽

Amino Acid Residues ◽

Dna Transposition ◽

Dead End ◽

Single Amino Acid Change ◽

Induced Pluripotent

Abstract The Sleeping Beauty (SB) transposon is an advanced tool for genetic engineering and a useful model to investigate cut-and-paste DNA transposition in vertebrate cells. Here, we identify novel SB transposase mutants that display efficient and canonical excision but practically unmeasurable genomic re-integration. Based on phylogenetic analyses, we establish compensating amino acid replacements that fully rescue the integration defect of these mutants, suggesting epistasis between these amino acid residues. We further show that the transposons excised by the exc+/int− transposase mutants form extrachromosomal circles that cannot undergo a further round of transposition, thereby representing dead-end products of the excision reaction. Finally, we demonstrate the utility of the exc+/int− transposase in cassette removal for the generation of reprogramming factor-free induced pluripotent stem cells. Lack of genomic integration and formation of transposon circles following excision is reminiscent of signal sequence removal during V(D)J recombination, and implies that cut-and-paste DNA transposition can be converted to a unidirectional process by a single amino acid change.

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Divergent genetic mechanism leads to spiny hair in rodents

10.1101/267385 ◽

2018 ◽

Author(s):

Gislene L. Gonçalves ◽

Renan Maestri ◽

Gilson R. P. Moreira ◽

Marly A. M. Jacobi ◽

Thales R. O. Freitas ◽

...

Keyword(s):

Amino Acid ◽

Genetic Basis ◽

Single Amino Acid ◽

Human Populations ◽

Wild Rodents ◽

Common Amino Acid ◽

Hair Morphology ◽

Single Amino Acid Change ◽

The Common ◽

Pocket Mouse

AbstractSpines, or modified hairs, have evolved multiple times in mammals, particularly in rodents. In this study, we investigated the evolution of spines in six rodent families. We first measured and compared the morphology and physical properties of hairs between paired spiny and non-spiny sister lineages. We found two distinct hair morphologies had repeatedly evolved in spiny rodents: hairs with a grooved cross-section and a second near cylindrical form. Compared to the ancestral elliptical-shaped hairs, spiny hairs had higher tension and stiffness, and overall, hairs with similar morphology had similar functional properties. To examine the genetic basis of this convergent evolution, we tested whether a single amino acid change (V370A) in the Ecdysoplasin A receptor (Edar) gene is associated with spiny hair, as this substitution causes thicker and straighter hair in East Asian human populations. We found that most mammals have the common amino acid valine at position 370, but two species, the kangaroo rat (non-spiny) and spiny pocket mouse (spiny), have an isoleucine. Importantly, none of the variants we identified are associated with differences in rodent hair morphology. Thus, the specific Edar mutation associated with variation in human hair does not seem to play a role in modifying hairs in wild rodents, suggesting that different mutations in Edar and/or other genes are responsible for variation in the spiny hair phenotypes we observed within rodents.

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Structural and functional analyses of Saccharomyces cerevisiae wild-type and mutant RNA1 genes

Molecular and Cellular Biology ◽

10.1128/mcb.9.7.2989-2999.1989 ◽

1989 ◽

Vol 9 (7) ◽

pp. 2989-2999

Author(s):

H M Traglia ◽

N S Atkinson ◽

A K Hopper

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Open Reading Frame ◽

Single Amino Acid ◽

Temperature Sensitive ◽

Wild Type ◽

Reading Frame ◽

Genomic Deletions ◽

Single Amino Acid Change ◽

Carboxy Terminal

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Faculty Opinions recommendation of A single amino acid change (Asp 53 --> Ala53) converts Survivin from anti-apoptotic to pro-apoptotic.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1018104.207609 ◽

2004 ◽

Author(s):

William Earnshaw

Keyword(s):

Amino Acid ◽

Amino Acid Change ◽

Single Amino Acid ◽

Single Amino Acid Change

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Single amino acid changes in the mumps virus haemagglutinin–neuraminidase and polymerase proteins are associated with neuroattenuation

Journal of General Virology ◽

10.1099/vir.0.009449-0 ◽

2009 ◽

Vol 90 (7) ◽

pp. 1741-1747 ◽

Cited By ~ 11

Author(s):

Tahir H. Malik ◽

Candie Wolbert ◽

Laura Nerret ◽

Christian Sauder ◽

Steven Rubin

Keyword(s):

Amino Acid ◽

Clinical Isolate ◽

Amino Acid Change ◽

Mumps Virus ◽

Site Directed Mutagenesis ◽

Single Amino Acid ◽

Supporting Evidence ◽

L Protein ◽

Single Amino Acid Change

It has previously been shown that three amino acid changes, one each in the fusion (F; Ala/Thr-91→Thr), haemagglutinin–neuraminidase (HN; Ser-466→Asn) and polymerase (L; Ile-736→Val) proteins, are associated with attenuation of a neurovirulent clinical isolate of mumps virus (88-1961) following serial passage in vitro. Here, using full-length cDNA plasmid clones and site-directed mutagenesis, it was shown that the single amino acid change in the HN protein and to a lesser extent, the change in the L protein, resulted in neuroattenuation, as assessed in rats. The combination of both amino acid changes caused neuroattenuation of the virus to levels previously reported for the clinical isolate following attenuation in vitro. The amino acid change in the F protein, despite having a dramatic effect on protein function in vitro, was previously shown to not be involved in the observed neuroattenuation, highlighting the importance of conducting confirmatory in vivo studies. This report provides additional supporting evidence for the role of the HN protein as a virulence factor and, as far as is known, is the first report to associate an amino acid change in the L protein with mumps virus neuroattenuation.

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