Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling

Background: Molecular chaperones recognize nonnative proteins and orchestra te cellular folding processes in conjunction with regulatory cofactors. How ever, not every attempt to fold a protein is successful, and misfolded prot eins can be directed to the cellular degradation machinery for destruction, Molecular mechanisms underlying the cooperation of molecular chaperones wi th the degradation machinery remain largely enigmatic so far. Results: By characterizing the chaperone cofactors BAG-1 and CHIP, we gaine d insight into the cooperation of the molecular chaperones Hsc70 and Hsp70 with the ubiquitin/proteasome system, a major system for protein degradatio n in eukaryotic cells. The cofactor CHIP acts as a ubiquitin ligase in the ubiquitination of chaperone substrates such as the raf-1 protein kinase and the glucocorticoid hormone receptor. During targeting of signaling molecul es to the proteasome, CHIP may cooperate with BAG-1, a ubiquitin domain pro tein previously shown to act as a coupling factor between Hsc/Hsp70 and the proteasome. BAG-1 directly interacts with CHIP; it accepts substrates from Hsc/Hsp70 and presents associated proteins to the CHIP ubiquitin conjugati on machinery. Consequently, BAG-1 promotes CHIP-Induced degradation of the glucocorticoid hormone receptor In vivo. Conclusions: The ubiquitin domain protein BAG-1 and the CHIP ubiquitin liga se can cooperate to shift the activity of the Hsc/Hsp70 chaperone system fr om protein folding to degradation. The chaperone cofactors thus act as key regulators to influence protein quality control.