The Lassa Virus Nucleoprotein Appears to Exhibit Conformational Control of Genome Binding

January 2013 SSRL Science Summary by Lori Ann White, SLAC Office of Communications

Surface representation of the Lassa virus nucleoprotein showing the RNA bound in between the two sub-domains, highlighting, in particular, a deep pocket that could be a prime target for anti-virals. (Courtesy of the Ollmann Saphire lab, The Scripps Research Institute.)

Lassa virus is endemic in Western Africa, and is the most common cause of viral hemorrhagic fever, infecting an estimated 300,000-500,000 people annually. It is also the hemorrhagic fever most frequently transported out of Africa to the United States and Europe. Understanding the key proteins of Lassa virus and any Achilles' Heels written into their protein structures will enable development of therapeutics for medical defense. Recent analysis of the crystal structure of the virus' RNA binding domain done at SSRL may have revealed one promising area of vulnerability.

This study revealed significant differences in the replication process of Lassa virus as compared to other negative-strand viruses as Ebola and measles, which also encode some or all of their genes in the negative direction. While the capsid enclosing Ebola or measles RNA is bound by a cofactor (often a phosphoprotein) during replication, the Lassa virus does not encode for such a protein; hence, the mechanism by which this common hemorrhagic fever virus controls genome binding during infection is not yet understood.

But an analysis using X-ray crystallography at SSRL's Beam Line 12-2 and Deuterium Exchange Mass Spectrometry (DXMS) suggested that RNA binding in Lassa is controlled through a gating mechanism of conformational changes. If this proves correct, the tight sequestering of RNA and likely conformational change needed for replication and transcription provide an excellent target for small molecules that either prevent RNA binding or prevent the necessary conformational changes. Thus, the published work provides a three-dimensional template by which a path may be found to a defense against a number of pathogens that threaten human health.

This work was supported by the Viral Hemorrhagic Fever Research Consortium and contract HHSN272200900049C (BAA-NIAID-DAIT-NIHAI2008031, EOS and VJW), grants AI077719 (JCT), AI047140 (JCT), GM093325 (VJW), RR029388 (VJW), an Investigators in Pathogenesis of Infectious Diseases award from the Burroughs Wellcome Fund (EOS), and the Skaggs Institute for Chemical Biology (EOS).

 

Primary Citation

K. M. Hastie, T. Liu, S. Li, L. B. King, N. Ngo, M. A. Zandonatti, V. L. Woods, Jr., J. C. de la Torre, E. O. Saphire, Crystal Structure of the Lassa Virus Nucleoprotein-RNA Complex Reveals a Gating Mechanism for RNA Binding", Proc. Natl. Acad. Sci. USA 108, 19365 (2011). [DOI: 10.1073/pnas.1108515108]

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Contacts

Kathryn Hastie and Erica Ollmann Saphire, The Scripps Research Institute