Murine norovirus protein NS1/2 aspartate to glutamate mutation, sufficient for persistence, reorients side chain of surface exposed tryptophan within a novel structured domain

Brendan N. Borin, Wei Tang, Timothy Nice, Broc T. Mccune, Herbert W. Virgin, Andrzej M. Krezel

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Compact viral genomes such as those found in noroviruses, which cause significant enteric disease in humans, often encode only a few proteins, but affect a wide range of processes in their hosts and ensure efficient propagation of the virus. Both human and mouse noroviruses (MNVs) persistently replicate and are shed in stool, a highly effective strategy for spreading between hosts. For MNV, the presence of a glutamate rather than an aspartate at position 94 of the NS1/2 protein was previously shown to be essential for persistent replication and shedding. Here, we analyze these critical sequences of NS1/2 at the structural level. Using solution nuclear magnetic resonance methods, we determined folded NS1/2 domain structures from a nonpersistent murine norovirus strain CW3, a persistent strain CR6, and a persistent mutant strain CW3D94E. We found an unstructured PEST-like domain followed by a novel folded domain in the N-terminus of NS1/2. All three forms of the domain are stable and monomeric in solution. Residue 94, critical for determining persistence, is located in a reverse turn following an α-helix in the folded domain. The longer side chain of glutamate, but not aspartate, allows interaction with the indole group of the nearby tryptophan, reshaping the surface of the domain. The discrimination between glutamyl and aspartyl residue is imposed by the stable tertiary conformation. These structural requirements correlate with the in vivo function of NS1/2 in persistence, a key element of norovirus biology and infection.

Original languageEnglish (US)
Pages (from-to)1200-1209
Number of pages10
JournalProteins: Structure, Function and Genetics
Volume82
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Norovirus
Aspartic Acid
Tryptophan
Glutamic Acid
Mutation
Viruses
Conformations
Proteins
Genes
Nuclear magnetic resonance
Viral Genome
Sequence Analysis
Magnetic Resonance Spectroscopy
Infection
indole

Keywords

  • Helix-strand-helix
  • MNV
  • PEST motif
  • Polyprotein
  • Protein NMR
  • Side chain rotamers

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

Murine norovirus protein NS1/2 aspartate to glutamate mutation, sufficient for persistence, reorients side chain of surface exposed tryptophan within a novel structured domain. / Borin, Brendan N.; Tang, Wei; Nice, Timothy; Mccune, Broc T.; Virgin, Herbert W.; Krezel, Andrzej M.

In: Proteins: Structure, Function and Genetics, Vol. 82, No. 7, 2014, p. 1200-1209.

Research output: Contribution to journalArticle

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