What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators

Abstract

In humans, the family of Bcl‐2 associated athanogene (BAG) proteins includes six members characterized by exceptional multifunctionality and engagement in the pathogenesis of various diseases. All of them are capable of interacting with a multitude of often unrelated binding partners. Such binding promiscuity and related functional and pathological multifacetedness cannot be explained or understood within the frames of the classical “one protein–one structure–one function” model, which also fails to explain the presence of multiple isoforms generated for BAG proteins by alternative splicing or alternative translation initiation and their extensive posttranslational modifications. However, all these mysteries can be solved by taking into account the intrinsic disorder phenomenon. In fact, high binding promiscuity and potential to participate in a broad spectrum of interactions with multiple binding partners, as well as a capability to be multifunctional and multipathogenic, are some of the characteristic features of intrinsically disordered proteins and intrinsically disordered protein regions. Such functional proteins or protein regions lacking unique tertiary structures constitute a cornerstone of the protein structure‐function continuum concept. The aim of this paper is to provide an overview of the functional roles of human BAG proteins from the perspective of protein intrinsic disorder which will provide a means for understanding their binding promiscuity, multifunctionality, and relation to the pathogenesis of various diseases.

What Is Parvalbumin for?

“…Taken together, data presented in this review indicate that PAs can serve as illustrative examples of the "protein structure-function continuum" model [144][145][146][147][148][149] based on the proteoform concept, which suggests that a single gene can encode for multiple structurally and functionally distinct protein molecules-proteoforms, originating as a result of alternative splicing and PTMs [150]-due to the presence of intrinsic disorder and related capability to undergo functional disorder-to-order transitions, as well as because of the structural perturbations induced by functioning [144]. In fact, it is clear that during their functional life, PAs have at least two global possibilities to undergo disorder-to-order transitions, first at binding of metal ions leading to the stabilization of the EF-hands and overall protein fold, and second, at interaction with the partner proteins.…”

The Moonlighting Function of Soybean Disordered Methyl-CpG-Binding Domain 10c Protein

“…By the bioinformatical analysis, the GmMBD10c protein was predicted to be disordered and form a protein-protein interaction network with other proteins. Most IDPs can protect target proteins through the chaperone function, similar to BSA [46,47]. In addition, IDPs can play protective roles through a molecular shield, where they inhibit the aggregation of stress-sensitive proteins without binding to the target protein [48,49].…”

Corelating the molecular structure of BAG3 to its oncogenic role

“…BAG3 is being studied by researchers worldwide considering its high binding promiscuity and potential to participate in a broad spectrum of interactions with multiple binding partners. Ability of BAG3 to interact with multiple interacting partners is responsible for pathogenesis of various diseases particularly cancer (Marzullo et al, 2022) (Table 1 and Figure 1).…”

“…Ability of BAG3 to interact with multiple interacting partners is responsible for pathogenesis of various diseases particularly cancer (Marzullo et al, 2022) (Table 1 and Figure 1).…”