Molecular Study of Bag Domains: A New Motif in Prostate Cancer
Abstract
The "BAG" domain is found in BAG family proteins and may have relevance to prostate cancer resistance to hormone-ablative and anti-androgen therapy. It promotes tumor survival and aggressiveness through a variety of mechanisms, including interactions with the anti-apoptotic protein Bcl-2 and Hsp70/Hsc70 molecular chaperones. Using NMR spectroscopy and' computational methods, we have determined the structure of the BAG domain from BAG4 and compared it with its counterpart in BAG1. The difference is striking, and the structural comparison defines two subfamilies of human BAG proteins. One subfamily includes BAG1, and the other is represented by BAG3, BAG4 and BAG5 proteins. BAG domains from both BAG1 and BAG4 are three-helix bundles; however, in BAG1, each helix in this bundle is three to four turns longer than its counterpart in BAG4, which increases the length of the domain by one-half. We have also investigated the interactions of BAG domains with Hsp70/Hsc70 proteins, using NMR and site-directed mutagenesis. Despite their distinct sizes, BAG domains from BAGI and BAG4 interact with Hsc70 in an analogous manner. Our structural studies provide context for functional investigations and enable us to better understand the role of BAG proteins at the molecular level.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA419189
Entities
People
- Klara Briknarova
Organizations
- Sanford Burnham Prebys Medical Discovery Institute