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

Peter Nguyen,Kyle Hess,Dat Le,Christina M Chavez,Carolina Briseno,Larissa Smulders,Nikolas Nikolaidis

doi:10.3390/ijms21249701

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.

Highlights

All living species cope with their ever-changing environments by activating the cellular stress response (CSR) [1]
These analyses revealed that the single nucleotide polymorphisms (SNPs) density is unequally distributed within the BAG1 gene, and the ratio of non-synonymous/synonymous SNPs is significantly higher than 1 in the BCL2-associated athanogene (BAG) domain region, which is an indication of positive selection
We sought to determine the origin of BAG-1 in eukaryotes

Summary

Introduction

All living species cope with their ever-changing environments by activating the cellular stress response (CSR) [1]. Several HSPs are molecular chaperones, playing a pivotal role in protein homeostasis under pathological and stressful conditions by supporting protein folding and refolding, and protein transportation across various membranes [2] These proteins inhibit apoptotic pathways and promote various immune responses by recruiting cytokines and anti-inflammatory effectors [3], and have been associated with several diseases, including cancer, cardiovascular, and neurodegenerative diseases [4,5,6]. In addition to their indispensable intracellular functions, several HSPs are found at the plasma membrane [7,8,9] and the extracellular environment, where they function in cell signaling and immunity [10,11,12]. HSPs are diverse in function, structure, and domain organization and are usually separated into families according to their molecular size [2]

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