NIH Scientists See Retrovirus Capsid Pentamer for First Time
For the first time, scientists can see an elusive protein that
forms part of the shell of a retrovirus—a finding that may help
in the development of therapies to disrupt the functioning of retroviruses,
which include the HIV/AIDS virus. The study, led by scientists at
the National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS), part of the National Institutes of Health, appears
in the current issue of the journal Nature.
The target of the research was a retrovirus capsid pentamer protein—a protein
composed of five subunits that forms part of the capsid, the shell
containing the nuclear material of a retrovirus. To date, scientists
have only been able to visualize capsid hexamer proteins, which are
composed of six subunits. Since structure often impacts function
on the molecular scale, these findings may further our understanding
of capsid assembly in retroviral replication and may lead to interventions
to disrupt it.
The NIAMS scientists, led by Alasdair Steven, Ph.D., a senior investigator in
the Laboratory of Skin Biology of the NIAMS ’ Intramural Research
Program, and in collaboration with scientists from The Pennsylvania
State University College of Medicine in Hershey, studied a retrovirus
called Rous sarcoma virus (RSV), a cancer-causing virus found in
chickens. However, since many retroviruses have similar proteins
in the capsid, the scientists’ work has implications for many retroviruses,
including other cancer-causing viruses and human immunodeficiency
Retroviruses vary in the shape and size of their capsids. HIV has a capsid in
the shape of an ice cream cone. RSV’ s capsid has an icosahedron
shape, with 20 sides and 12 points. Despite the fact that scientists
have only been able to visualize hexamer proteins in two-dimensional
sheets or tubes, they knew mathematically that pentamers had to exist
in order to create the various capsid shapes seen in retroviruses.
The scientists used a technique called cryo-electron microscopic analysis of
in vitro-assembled capsids from RSV to visualize the capsid proteins
in three dimensions. In short, they froze the capsid proteins, made
a cast of their shapes, and then used electron microscopy to simulate
a three-dimensional model of the shapes. They discovered the subunits
that make up the hexamer and pentamer proteins are practically identical
in shape and chemical make-up, and are also practically identical
to the subunits found in HIV capsid proteins. The scientists investigated
further to see how these subunits interacted to create such diverse
capsid protein shapes and sizes.
The answer had to do with tops and bottoms. Each protein subunit is like a balled-up
string with two ends. The top end is called the N-terminal domain
(NTD) and the bottom end is called the C-terminal domain (CTD). Each
subunit is connected to its neighboring two subunits through the
connection of the ends of the strings. This provides for three types
of binding: top to top (NTD-NTD), top to bottom (NTD-CTD), and bottom
to bottom (CTD-CTD). These different interactions determine the shapes
and sizes of the various capsid proteins. And, it is the combination
of these capsid proteins that determines the shapes and sizes of
the capsids themselves.
These findings contribute to our understanding of the structure, function, and
creation of retroviral capsids. Currently, research is investigating
the potential to disrupt capsid assembly during viral replication.
Discoveries in this area could lead to treatments to prevent or halt
the progression of a retroviral infection.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases,
a part of the Department of Health and Human Services' National Institutes of
Health, is to support research into the causes, treatment and prevention of arthritis
and musculoskeletal and skin diseases; the training of basic and clinical scientists
to carry out this research; and the dissemination of information on research
progress in these diseases. For more information about NIAMS, call the information
clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS
Web site at http://www.niams.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Reference: Cardone G, Purdy JG, Cheng N, Craven RC, Steven AC. “Visualization of a missing link in retrovirus capsid assembly.” Nature, Vol 457, 5 February 2009. DOI:10.1038/nature07724.
Note: On February 12, 2009 the first name listed in
the reference was changed from “Giovanni C” to “Cardone G” at the request
of the Institute.