PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Protein Folding and Misfolding: It's the Journey, Not the Destination
March 2015
CCR5 and HIV Infection
January 2015
HIV/AIDS: Pre-fusion Env Exposed
January 2015
HIV/AIDS: Slide to Enter
January 2015
Updating ModBase
January 2015
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Bacterial CDI Toxins
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Virology: A Bat Influenza Hemagglutinin
March 2014
Virology: Making Sensitive Magic
March 2014
Virology: Visualizing Cyanophage Assembly
March 2014
Virology: Zeroing in on HBV Egress
March 2014
March 2014
Cas4 Nuclease and Bacterial Immunity
February 2014
Microbial Pathogenesis: A GNAT from Pseudomonas
February 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Microbiome: The Dynamics of Infection
September 2013
Membrane Proteome: A Funnel-like Viroporin
August 2013
Infectious Diseases: A Pathogen Ubiquitin Ligase
May 2013
Infectious Diseases: A Shared Syringe
May 2013
Infectious Diseases: Determining the Essential Structome
May 2013
Infectious Diseases: Targeting Meningitis
May 2013
NDM-1 and Antibiotics
May 2013
Bacterial Hemophores
January 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Microbial Pathogenesis: NEAT Iron
January 2013
Membrane Proteome: Sphingolipid Synthesis Selectivity
December 2012
A signal sensing switch
September 2012
Gauging needle structure
July 2012
Anthrax Stealth Siderophores
June 2012
A Pseudomonas L-serine dehydrogenase
May 2012
Pilus Assembly Protein TadZ
April 2012
Making Lipopolysaccharide
January 2012
Superbugs and Antibiotic Resistance
December 2011
A change to resistance
November 2011
An effective and cooperative dimer
November 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
Breaking down the defenses
September 2011
Moving some metal
August 2011
Capsid assembly in motion
April 2011
Know thy enemy … structurally
October 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Hemolysin BL
January 2010
Unusual cell division
October 2009
Anthrax evasion tactics
September 2009
Toxin-antitoxin VapBC-5
September 2009
Antibiotic target
August 2009
July 2009
Tackling influenza
June 2009
You look familiar: the Type VI secretion system
June 2009
Unique SARS
April 2009
Anthrax stealth molecule
March 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Antiviral evasion
October 2008
SARS connections
September 2008
SARS Coronavirus Nonstructural Protein 1
June 2008

Research Themes Infectious diseases

An effective and cooperative dimer

SBKB [doi:10.1038/sbkb.2011.46]
Featured Article - November 2011
Short description: NMR studies reveal the dimer interface of the effector domain (ED) of NS1A from influenza A virus and provide insight into how dimerization of the ED provides cooperative dsRNA binding and other functions of NS1A.

Working model useful in guiding studies of the cooperative binding of NS1A to dsRNA. View into the dsRNA helical axis of a model of the complex between full-length NS1A and dsRNA (black). The RBD and ED domains are rendered as cylinders and surfaces, respectively. Image courtesy of James Aramini and Guy Montelione.

With the rise of new strains of influenza virus and the emergence of antiviral-resistant strains, identifying new targets for antiviral therapeutics is becoming increasingly important. One such target is the nonstructural protein 1 of influenza A (NS1A). NS1A binds nonspecifically to double-stranded RNA (dsRNA) through its N-terminal RNA-binding domain (RBD) and to a host of cellular proteins through its C-terminal effector domain (ED). These interactions allow the virus to evade the host antiviral system by affecting interferon-induced and other innate immune response pathways.

NS1A has been the focus of several recent structural studies. The ED has been shown to adopt a novel α-helix β-crescent fold that forms a homodimer. However, the biological dimer interface has remained controversial, as structures of the ED of NS1A from different influenza strains have revealed three different dimer interfaces.

Aramini, Ma, Montelione and colleagues (PSI NESG), in a PSI Community Outreach project with R. Krug at the University of Texas, Austin, have recently revealed the biologically relevant dimer of the ED from NS1A of H3N2 influenza A/Udorn/307/1972 (Ud) virus. They determined that the affinity for dimerization is relatively weak (micromolar range) and proceeded to map the dimer interface by NMR. Rotational correlation measurements, chemical shift mapping and NOE analysis all confirm a helix-helix dimer interface. These data are consistent with some, but not all, of the available crystal structures of the NS1A ED, resolving a controversy in the literature in which several alternative dimer interfaces have been observed in various crystal forms.

The authors went on to confirm the importance of a particular residue, Trp187, for dimerization. Mutation of Trp187 in the context of full-length Ud NS1A disrupts higher-order oligomerization and impairs its ability to bind to dsRNA. The mutant NS1A protein also shows reduced cooperativity in its binding of long stretches of dsRNA. On the basis of these results, Aramini and colleagues propose a model by which Ud NS1A forms a tube around the dsRNA, and the ED is involved in either cooperative interactions between NS1A dimers along the dsRNA, or in binding to other proteins, depending on the local NS1A, dsRNA and binding-partner concentrations.

This study highlights the ability of NMR to characterize weak dimers in solution, which are sometimes incorrectly characterized by crystallography as a result of lattice-packing effects. Furthermore, knowing the affinity for dimerization of the ED of Ud NS1A will be important for drug screening, as such experiments can be done under conditions at which the ED of Ud NS1A is monomeric.

Jennifer Cable


  1. J. M. Aramini, L.-C. Ma et al. The dimer interface of the effector domain of non-structural protein 1 from influenza A virus: an interface with multiple functions.
    J. Biol. Chem. 286, 26050-26060 (2011). doi:10.1074/jbc.M111.248765

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health