Moonlighting chaperone‐like activity of the universal regulatory 14‐3‐3 proteins

Abstract

The ubiquitous eukaryotic 14‐3‐3 proteins coordinate multiple cellular processes due to their well‐known regulatory function, which is based on specific recognition of phosphorylated motifs in their partners. In this context, 14‐3‐3 proteins have been called ‘chaperones’. Although in the classical meaning this is not fully correct, recent studies have revealed that they can indeed be an integral part of the protein quality control system, as they (a) display ATP‐independent anti‐aggregation (‘holdase’) activity, similar to that of the unrelated small heat shock proteins, (b) assist in clearing misfolded proteins by directing them to proteasomes or aggresomes, (c) cooperate with classical chaperones for substrate refolding, and also (d) are associated with neurodegenerative disorders by affecting aggregation of tau, prion protein, α‐synuclein, huntingtin, etc. Importantly, these activities are usually independent of substrate phosphorylation and therefore should be considered as distinct, ‘moonlighting’ functions of 14‐3‐3 proteins that mimic and complement the functions of dedicated molecular chaperones. Although the precise mechanism of this activity is still unknown, it has been shown that it is not dependent on the unstructured C‐terminal region or the amphipathic phosphopeptide‐binding groove. However, since disassembly of 14‐3‐3 dimers significantly increases their chaperone‐like activity, the dimer interface, located in the N terminus, possessing a high disorder propensity and pronounced hydrophobicity, is likely to be involved. Various factors affecting the oligomeric status of 14‐3‐3 proteins can thus regulate the balance between regulatory phosphomotif binding and genuine chaperone‐like activity. Understanding the latter mode of 14‐3‐3 functioning is fundamental to defining the underlying molecular mechanisms for a range of human disorders.

Current Insights to Regulation and Role of Telomerase in Human Diseases

“…hTERT can interact with proteins such as chaperone p23, HSP90, TEP1, Ku, hEST1, KIP, PinX1, which regulate post-translational modifications, telomerase assembly, localization and activity [30]. The interaction of 14-3-3, which is a chaperone-like protein [31], with hTERT, for example, regulates TERT intracellular localization and enhances its nuclear localization [32]. Mutations in the RNA binding domain (TRBD) may also impair the enzyme activity [33].…”

14‐3‐3 protein masks the nuclear localization sequence of caspase‐2

“…In addition, Ser 340 phosphorylation by Cdk1 kinase has also been shown to prevent caspase-2 activation during normal mitosis [15]. 14-3-3 proteins, highly homologous dimeric molecules present in all eukaryotic organisms, are the main regulators of key cellular processes such as apoptosis, signal transduction, cell cycle regulation, or tumorigenesis [16][17][18][19]. More than 2000 14-3-3 protein-binding partners have been predicted and several hundred have been experimentally validated thus far [20,21].…”

Moonlighting proteins: putting the spotlight on enzymes

“…41 That small sequence changes can have drastic effects on function has been documented for a number of proteins found in organisms ranging from microorganisms to plants and animals. [42][43][44][45][46] Once a sequence change is established, the change may affect existing protein interaction partners, or may introduce a new interaction site. The cytoplasm of a cell is crowded with macromolecules and proteins at any given time.…”