BAG2 structure, function and involvement in disease

Abstract

Bcl2-associated athanogene 2 (BAG2) shares a similar molecular structure and function with other BAG family members. Functioning as a co-chaperone, it interacts with the ATPase domain of the heat shock protein 70 (dHsp70) through its BAG domain. It also interacts with many other molecules and regulates various cellular functions. An increasing number of studies have indicated that BAG2 is involved in the pathogenesis of various diseases, including cancers and neurodegenerative diseases. This paper is a comprehensive review of the structure, functions, and protein interactions of BAG2. We also discuss its roles in diseases, including cancer, Alzheimer's disease, Parkinson's disease and spinocerebellar ataxia type-3. Further research on BAG2 could lead to an understanding of the pathogenesis of these disorders or even to novel therapeutic approaches.

Keywords: Alzheimer’s disease; BAG2; Carcinoma; Molecular chaperones; Parkinson’s disease; Spinocerebellar ataxia type-3.

Fig. 1

Schematic representation of the domain structure of BAG family proteins. All six reported BAG proteins contain a BAG domain at their C-terminus. The BAG2 C-terminal domain is defined as the BNB domain. There is a coiled coil domain near the amino terminus. Domains in the other BAG-family proteins include a nuclear localization signal (NLS), ubiquitin-like (UBL) domain, WW domain, DUF domain, and proline-rich regions (PXXP)

Fig. 2

BAG2 interacts with the molecular chaperone Hsp70, which plays a prominent role in protein homeostasis. BAG2 accelerates ADP dissociation from Hsp70 and promotes Hsp70-mediated protein refolding. BAG2 is also an inhibitor of the Hsp70-binding E3 ubiquitin ligase CHIP and inhibits CHIP-mediated ubiquitination. Importantly, BAG2 inhibits tau ubiquitination, delivering phosphorylated tau to the proteasome for degradation via a ubiquitin-independent pathway. (+) indicates promoting, (−) indicates inhibiting, Ub indicates ubiquitin and UPS indicates the ubiquitin–proteasome system

Fig. 3

The relationship between BAG2 and disease. BAG2 gene expression is regulated by various biochemical factors at the level of transcription and translation. BAG2 interacts with other proteins to regulate diverse biological and pathological processes, such as cell apoptosis, tumor growth, neuronal differentiation, stress response, cell cycle and signal transduction. Therefore, BAG2 may play an important role in the pathogenesis of diseases, including cancer and neurodegenerative disorders. (+) indicates promoting, (−) indicates inhibiting and UPS indicates the ubiquitin–proteasome system