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The BAG (Bcl-2-associated athanogene) family was first identified as a group of proteins that prevent cell death through their interaction with Bcl-2. They share a conserved region at their C-terminal. BAG2 shares a similar molecular structure and function with other BAG family members. BAG2 is an Hsp70/Hsc70 molecular chaperone-interacting protein originally discovered using yeast two-hybrid screening. It is composed of 211 amino acids. Although the C-terminus of BAG2 is classified as a BAG domain, researchers have found that it shares a low level of homology with other BAG domains. After using crystallographic technology, found that the BAG2 C-terminal domain adopts a novel dimeric structure in the Hsp70/Hsc70 binding mode, and that this structure differs greatly from those of known BAG domains and from those of other Hsp70/Hsc70 nucleotide exchange factors (NEF). Moreover, they definitively showed clientbinding site overlap with the Hsp70/Hsc70-binding site.
Functions of BAG2 BNB Domain
The BAG2 BNB (BAG2 C-terminal domain with its atypical dimeric structure is considered a unique Hsp70/Hsc70–NEF and proposed that it be defined as the brand new BAG domain) domain harbors dual functions of nucleotide exchange and client binding. When binding with ATP, Hsp70 exhibits low substrate affinity, whereas in the ADP-bound state, it has high affinity for its substrates. Heat shock protein 70-mediated protein refolding is limited by the inherent low nucleotide exchange rate, efficient protein refolding requires interaction between Hsp70 and NEFs. Previous studies have indicated that BAG2 binds with high affinity to the ATPase domain of Hsp70 and inhibits its chaperone activity in a hip repressible manner. The NEF function of BAG2, which accelerates the ATPase cycle, can affect folding, aggregation and degradation reactions in different ways depending on the associated client and the cooperation with other chaperones and co-chaperones. Apart from being NEF, BAG2 also has an intrinsic companion client binding activity. In addition to the formation of complexes of BAG-Hsp70, BAG proteins functionally interact with a variety of binding partners and coordinate different cellular processes such as stress signaling, cell division, cell death, and cell differentiation. Additionally, BAG2 is an inhibitor of E3 ubiquitin ligase CHIP (carboxyl-terminus of Hsp70-interacting protein) that binds Hsp70. BAG2 NTD inhibits CHIP-mediated ubiquitination.
Fig. 1. BAG2 interacts with the molecular chaperone Hsp70, which plays a prominent role in protein homeostasis. (Qin et al. Cellular & Molecular Biology Letters. 2016).
Interaction with HSP70-binding E3 ubiquitin ligase CHIP
There are at least two domains in the CHIP: a u-box domain that interacts with the ubiquitin conjugated enzyme E2, and a TPR domain that is linked to heat shock protein 70 and Hsp90. Previous studies have addressed the relationship between BAG2 and heat shock protein 70-associated ubiquitin ligase. BAG2 homologs are present in the genome of organisms with CHIP, but not in fungi lacking CHIP. In vivo, BAG2 colocalizes with CHIP, especially within the endoplasmic reticulum. Use a binding test, Dai et al. was shown that BAG2 binds to CHIP as part of the Hsc70 ternary complex. They also indicated that BAG2 is a potent and specific inhibitor of CHIP-dependent ubiquitin ligase activity.
Further investigation proved that BAG2 NTD inhibits the ubiquitin ligase activity of CHIP by abrogating CHIP/E2 cooperation and stimulates the chaperone-assisted maturation of CFTR. Researchers held that this inhibitory activity is dependent on localizing to Hsp70-CHIP chaperone complexes through the BAG2 BNB–Hsp70-NBD association. Given this, additional studies on the BAG2 NTD and full-length BAG2 are necessary to better understand their mechanisms and intracellular functions. Further studies have shown that BAG2 NTD inhibits the ubiquitin ligase activity of the CHIP through destroy the cooperation of the CHIP/E2 and stimulates the maturity of CFTR chaperone-assisted maturation of CFTR. The researchers believe that this inhibitory activity is dependent on the localization to the Hsp70-CHIP chaperone complexes by the BAG2 BNB.
Interaction with other related proteins
BAG2 is phosphorylated by MAPK-activated protein (MAPKAP) kinase 2, which is known as the major p38 MAPK substrate, which mediates several p38 MAPK-dependent processes. This phosphorylation is part of a new signaling pathway involved in extracellular stress responses. MAPK cascade integrates and processes various extracellular signals through phosphorylation matrix. Various stresses, endotoxins and cytokines activate P38, which phosphorylates and regulates downstream protein kinases to regulate various intracellular processes. Enrichment of phosphorylated proteins, fluorescence two-dimensional differential gel electrophoresis and mass spectrometric identification of proteins, Ueda et al. found that BAG2 is a candidate for a target for p38 MAPK-dependent phosphorylation in response to anisomycin treatment in HeLa cells. They confirmed that phosphorylation of BAG2 need MAPKAP kinase 2 in vitro and in vivo. Hsp90 is required for ERK1/2 activation and associates with BAG2. Previous studies have shown that BAG2 overexpression reverses p38-dependent nicotine-induced tau phosphorylation. This may be due to inhibition of ERK1/2 interaction with Hsp90 by BAG2-mediated phosphorylation tau, which depend on BAG2 phosphorylate p38/MAPKAPK2.
Fig. 2. BAG2 switch the p38-dependent effects of nicotine on tau phosphorylation levels. (Adriele et al. Experimental Neurology. 2016)