Origin and Evolution of the Human Bcl2-Associated Athanogene-1 (BAG-1)

Abstract

Molecular chaperones, particularly the 70-kDa heat shock proteins (Hsp70s), are key orchestrators of the cellular stress response. To perform their critical functions, Hsp70s require the presence of specific co-chaperones, which include nucleotide exchange factors containing the BCL2-associated athanogene (BAG) domain. BAG-1 is one of these proteins that function in a wide range of cellular processes, including apoptosis, protein refolding, and degradation, as well as tumorigenesis. However, the origin of BAG-1 proteins and their evolution between and within species are mostly uncharacterized. This report investigated the macro- and micro-evolution of BAG-1 using orthologous sequences and single nucleotide polymorphisms (SNPs) to elucidate the evolution and understand how natural variation affects the cellular stress response. We first collected and analyzed several BAG-1 sequences across animals, plants, and fungi; mapped intron positions and phases; reconstructed phylogeny; and analyzed protein characteristics. These data indicated that BAG-1 originated before the animals, plants, and fungi split, yet most extant fungal species have lost BAG-1. Furthermore, although BAG-1’s structure has remained relatively conserved, kingdom-specific conserved differences exist at sites of known function, suggesting functional specialization within each kingdom. We then analyzed SNPs from the 1000 genomes database to determine the evolutionary patterns within humans. These analyses revealed that the SNP density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BAG domain region, which is an indication of positive selection. To further explore this notion, we performed several biochemical assays and found that only one out of five mutations tested altered the major co-chaperone properties of BAG-1. These data collectively suggest that although the co-chaperone functions of BAG-1 are highly conserved and can probably tolerate several radical mutations, BAG-1 might have acquired specialized and potentially unexplored functions during the evolutionary process.

On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis

“…Besides their BAG domain, they also carried an ubiquitin‐like (UBL) domain. This is in concert with previous investigations of BAG1's evolution 20 …”

“…This is in concert with previous investigations of BAG1's evolution. 20 Interestingly, fungi BAG1 orthologues (Shizosaccharomyces pombe BAG101 and Amanita muscaria (Amu) BAG1) appear as an outgroup of class II BAGs. Other class II BAGs only occur in Vertebrata and include orthologues of human BAG3, BAG4, and BAG5.…”

Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7

“…To substantiate the above-described evolutionary patterns and clarify the origins of the Plekha4/5/6/7 vertebrate genes, we sought to investigate their exon-intron organization and syntenic relationships, as performed previously for other gene families ( Nikolaidis and Nei, 2004 ; D'Aniello et al, 2008 ; Coppola et al, 2019 ; Nguyen et al, 2020 ).…”

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

“…The lack of an obvious toxic effect of A4B17 in human cells, mice and in the zebrafish model reflects selective engagement of the compound to the BAG pocket in these species. BAG1 is a very conserved protein and the BAG domain, especially the amino acids that form the BAG pocket into which A4B17 docks ( Kuznik et al., 2021 ), is conserved in human, mice and zebrafish ( Nguyen et al., 2020 ).…”