The gene encompasses 33450 bases, 4 exons.

2608 nucleotides mRNA.

Chromosome 10: 121442639-121443335 reverse strand. Name: RP11-179H18.7-001; transcript: ENST00000441872.
Chromosome 10: 121435973-121436791 forward strand. Name: PGOHUM00000238940; parent protein: ENSP00000358081; parent gene: ENSG00000151929.
Variant: OTTHUMT00000050663. Exons: 5. Transcript length: 1146 bps. Translation length: 325 residues.

575 amino acids. 74 kDa protein, belonging to the evolutionary conserved family of BAG domain-containing proteins.

Under physiological conditions, BAG3 expression appears to be restricted to few cell types including skeletal muscle cells and cardiomyocytes (Hishiya et al., 2010; De Marco et al., 2011; De Marco et al., 2013). Its expression, however, can be induced in different normal cell types (leukocytes, epithelial, glial and retinal cells) by a variety of stressors, such as oxidants, high temperature, serum deprivation, and it is thought to contribute to stress resistance (Rosati et al., 2007; Pagliuca et al., 2003; Rosati et al., 2009; Ammirante et al., 2010). In contrast to normal cells, BAG3 expression is abundant in several primary tumors or tumor cell lines, where it is thought to give a survival advantage (Rosati et al., 2011). Among those melanoma cells, pancreatic adenocarcinoma cells, colon cancer, liver cancer, T-lynph Jurkat cancer, leukemias, kidney HEK-293, Lung A549, prostate cancer LnCap, cervix cancer Hela, bone cancer U20S, breast cancer cells MCF7.

BAG3 is mainly a cytoplasmatic protein, particularly concentrated in the rough endoplasmic reticulum; a slightly different molecular weight, a doublet form or a nuclear localisation can be observed in some cell types and/or following cell exposure to stressors. BAG3 protein is also released from stressed cardiomyocytes and Pancreatic Adeno Carcinoma cells (PDAC) and can be detected in sera of patients with chronic heart failure (HF) or PDAC (De Marco et al., 2013; Falco et al., 2013), as well as in cells surnatants.

Through its BAG domain, BAG3 protein binds with high affinity to the ATPase domain of Hsc70 and regulates its chaperone activity in a Hip-modulated manner; through its PXXP region, BAG3 binds to the SH3 domain of PLC-gamma and forms an epidermal growth factor (EGF)-regulated ternary complex; the proline-rich repeat appears to be involved in regulating cell adhesion and migration, through an indirect effect on focal adhesion kinase (FAK) and its downstream partners; BAG3 knockout mice develop a fulminant myopathy; downmodulation of BAG3 protein levels enhance cell apoptotic response to several inducers, while hyperexpression protects cells from apoptosis. BAG3 levels increase during myoblast differentiation, suggesting that its biological role is relevant for differentiated myocytes and not for immature cells. This is in agreement with the observation that BAG3 deletion causes a lethal cardiomyopathy not in embryos, but in postnatal mice. BAG3 mutations may cause abnormal Z-disc assembly and sensitization to apoptosis in cultured cardiomyocytes. More recently it has been shown that BAG3 is essential for homeostasis of mechanically stressed cells. BAG3 is in fact an important component of the chaperone-assisted autophagy (CASA) pathway leading to selective lysosomal degradation of unfolded proteins. In muscle cells the CASA machinery is located at the Z-disk and appears to be essential for disposal of unfolded mechano-sensors and cytoskeleton proteins resulting from mechanical tension. Impairment of the CASA machinery results in z-disk disruption in contracting muscles (Ulbricht et al., 2013; Ulbricht and Höhfeld, 2013).

Other members of BAG family.

Several reports associate BAG3 mutations with myopathy. A mutated form of BAG3, i.e. heterozygous Pro209Leu, causes childhood cardiomyopathy and a severe and progressive muscle weakess (Selcen et al., 2009). Non-synonymous BAG3 SNPs or others truncated BAG3 forms were reported to correlate with familiar dilated cardiomyopathy (Villard et al., 2011) and stress-cardiomyopathy also known as Takotsubo cardiomyopathy (Citro et al., 2013). Finally, two heterozygous BAG3 gene mutations, which cause abnormal Z-disc assembly and increased sensitivity to apoptosis in cultured cardiomyocytes, were identified in patients with familial DCM (Arimura et al., 2011).