17 / 101
Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts
12
The Molecular Tool-Kit of the Filoviruses
E O. Saphire
1
, Z A. Bornholdt
1
, M L. Fusco
1
, D M. Abelson
1
, R N. Kirchdoerfer
1
, J E. Lee
1
, T
Hashiguchi
1
, C R. Kimberlin
1
, J M. Dias
1
, J F. Bruhn
1
, S Bale
1
, A Zhang
1
, P Halfmann
2
, T
Noda
3
, Y Kawaoka
2,3
, J M. Dye
4
, K Chandran
5
.
1
The Scripps Research Institute, La Jolla, CA, USA,
2
University of Wisconsin, Madison, WI,
USA,
3
University of Tokyo, Tokyo, Japan,
4
USA Army Medical Research Institute for Infectious
Diseases, Frederick, MD, USA,
5
Albert Einstein College of Medicine, Bronx, NY, USA.
Viruses can be under tremendous pressure for economy of genomic information. As a result,
evolution has compelled viral proteins to offer the most functional “bang” for the polypeptide
“buck.” The ability of viruses to maximize functionality from a limited genome, and to evolve
their functionalities in real time offers us fundamental insights into the capabilities and plasticity
of proteins in general.
Filoviruses have a compact genome of only 7 genes. Consequently, each protein is critical, many
perform multiple functions, and some actually rearrange their structures to achieve those new
functions. By employing a variety of structural and biophysical methods, we can illuminate this
compact, but highly versatile tool-kit and gain fundamental insights into the biology of entry,
immune evasion, replication and assembly. We use this information to decipher the collaborative
roles of these proteins in pathogenesis and devise concrete strategies for medical defense.
Crystal structures are now available of the metastable, viral-surface glycoproteins of the Ebola,
Sudan and Marburg viruses. These images illuminate how the receptor-binding sites become
unsheathed in the host endosome, map the epitopes of neutralizing and non-neutralizing
antibodies and provide the roadmap for medical defense against viral entry.
Proteins in the filovirus nucleocapsid complex play dual roles in viral replication and
immunosuppression. Structure-function studies illuminate how these molecules control assembly
and genome packaging while preventing cellular detection of the invading pathogen.
Other work, on the filovirus matrix protein VP40, challenges the pervading “one gene – one
structure” hypothesis of molecular biology – by proving that a single polypeptide sequence can
adopt different three-dimensional structures – each of which plays a completely separate and yet
equally essential biological role. This discovery provides a novel mechanism to explain how
RNA viruses can achieve multifarious functions using elementary genomes.