BAG-1--a nucleotide exchange factor of Hsc70 with multiple cellular functions

Abstract

BAG-1 (Bcl-2-associated athanogene) is a multifaceted protein implicated in the modulation of a large variety of cellular processes. Elucidating the molecular mechanisms that underlie the cellular functions of BAG-1 becomes an increasingly important task, particularly in light of the growing evidence connecting aberrant BAG-1 expression to certain human cancers. A common element of the remarkable functional diversity of BAG-1 appears to be the interaction with molecular chaperones of the Hsp70 family. In fact, BAG-1 functions as a nucleotide exchange factor of mammalian cytosolic Hsc70, thereby triggering substrate unloading from the chaperone. In addition, recent findings reveal an association of BAG-1 with the proteasome, which suggests a role in coordinating chaperone and degradation pathways.

Fig 1.

Domain structure of BAG-1 (Bcl-2–associated athanogene) isoforms, of carboxyl terminus of Hsc70 interacting protein (CHIP), and of the model for the functional cooperation of the 2 cochaperones during the sorting of Hsc70-bound substrate proteins to the proteasome for degradation. Four isoforms of BAG-1 have been detected, which differ with regard to the length of their amino termini. Several structural elements are located at the amino terminus, including a nuclear localization signal (NLS), a deoxyribonucleic acid–binding motif (DNA), and multiple repeats of the hexapeptide motif TRSEEX. All isoforms possess a central ubiquitin-like domain used for proteasome binding and a carboxyl terminal BAG domain, which mediates binding and regulation of Hsc70. CHIP possesses a triple TPR domain that, together with an adjacent charged region, forms a binding site for Hsc70 and Hsp90. A central coiled coil domain (cc) may be involved in protein-protein interactions. The carboxyl terminal U-box is required for the ubiquitin ligase activity of CHIP and seems to mediate binding to ubiquitin-conjugating enzymes of the Ubc4/5 family. Association of CHIP with the carboxyl terminal domain of Hsc70 (C) gives rise to a chaperone complex that mediates sorting to the proteasome. At the same time, BAG-1 binds to the adenosine triphosphatase domain of Hsc70 (ATPase) and in addition contacts CHIP directly. The ubiquitin-like domain of BAG-1 (ubl) remains exposed in the formed complex and serves as a proteasomal sorting signal. Subunit and domain arrangement in the complex remains to be determined experimentally