An unexpected result was that there was more than one VPS37 protein in human cells. In fact, there was a family of four different VPS37 proteins that the scientists named VPS37A-D. Says Sundquist, "We do not yet fully understand why humans have four different VPS37 proteins, but we assume that this provides greater potential for regulating the MVB pathway, which is responsible for targeting a number of important cellular proteins for lysosomal destruction."
The scientists focused their efforts on one of the proteins,VPS37B, and found that it binds to TSG101 through a conserved sequence of amino acids that is also present in all of the other Vps37 proteins. They also showed that VPS37B is a subunit of the human ESCRT-I complex, and that it is capable of recruiting the ESCRT-I complex to support HIV budding in vivo.
Sundquist and colleagues also managed to identify regions of TSG101 that bind to VPS28 and VPS37, and showed that theVPS28 binding region is essential for HIV-1 budding. This information could potentially be used to develop drugs that target these binding regions and disrupt HIV-1 budding, preventing infection from spreading.
These results were independently confirmed by another research group led by Harald Stenmark of the Norwegian Radium Hospital in Montebello, Norway. Stenmark's group also discovered the same group of human VPS37 proteins and published their results in the September issue of Molecular Biology of the Cell.
Says Sundquist, "In a general sense, I think that it is important to identify all of the cellular proteins that are involved in HIV replication, and it appears likely that the newly identified VPS37 proteins play a direct role in HIV budding. In principle, the VPS37 proteins are therefore potential new drug targets, though of course many significant hurdles remain to be overcome, such as inhibitor screening and potential problems with ce
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Contact: Nicole Kresge
nkresge@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology
1-Sep-2004