GAG DOMAINS REQUIRED FOR RETROVIRUS ASSEMBLY

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from Applicant's Abstract): Not enough is known about
retroviruses to prevent the diseases they cause, and a better understanding
of their replication cycle is needed. Some of the least understood steps
are those of virion assembly. The Gag protein encoded by each retrovirus
plays the central role in assembly. Expression of Gag results in the
formation and release of virus-like particles from the plasma membrane, even
in the absence of all the other components encoded by the virion.
Experiments described in the application continue to focus on Gag-mediated
particle assembly. During the previous funding period, the applicant's lab
dissected the Gag proteins of Rous sarcoma virus (RSV) and HIV. In each,
three small functional domains were found that are essential for budding:
the M (membrane-binding), I (interaction), and L (late) domains.
Surprisingly, these domains turned out to be fully interchangeable between
the two Gag molecules even though they share no sequence homology.
Moreover, the order of M, I, and L is different in each case. It is
important to learn how the parts of the "particle-making machine" work to
direct the budding process. Towards this end, five Specific Aims are
proposed. The first aim is focused on the structure and function of the M
domain of RSV, shown to be very different from that of HIV. The immediate
goal is to determine the three dimensional structure of this domain by NMR
and crystallography, and to test the resulting models about how it works.
Alternative strategies are proposed toward this end. The second aim
addresses the question of how proteins destined to reside on the cytoplasmic
faces of membranes specifically find their targets. For this, a
complementation assay will be exploited that was developed in the previous
funding period. Aims 3 and 4 address specific questions regarding the I and
L domains. The last aim addresses the determinants that control the rate of
budding and the sizes of particles that are produced. A variety of
approaches o find host proteins that potentially participate in the budding
process are also proposed within several of the specific aims.
StatusFinished
Effective start/end date9/15/915/31/01

Funding

  • National Cancer Institute
  • National Cancer Institute: $396,041.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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