The evolution of protein moonlighting: adaptive traps and promiscuity in the chaperonins

Abstract

Moonlighting proteins exhibit functions that are alternative to their main role in the cell. Heat-shock proteins, also known as molecular chaperones, are now recognized for their wide range of activities in and/or outside the cell, being prominent examples of moonlighting proteins. Chaperonins are highly conserved molecular chaperones that fold other proteins into their native conformation allowing them to carry out essential functions in the cell. Activities alternative to folding have been reported for the chaperonin (Cpn) 60 protein. Preservation of various alternative functions in one protein conflicts with the optimization of each of the functions. What evolutionary mechanisms have allowed the persistence of moonlighting proteins, and in particular the chaperonins, remains a mystery. In the present article, I argue that mechanisms that increase the resistance of phenotypes to genetic and environmental perturbations enable the persistence of a reservoir of genetic variants, each potentially codifying for a distinct function. Gene duplication is one such mechanism that has characterized the expansion and has been concomitant with the emergence of novel functions in these protein families. Indeed, Cpn60 performs a large list of folding-independent functions, including roles in the transmission of viruses from insects to plants and stimulation of the immune system, among others. In addition to the innovation promoted by gene duplication, I discuss that the Cpn60 protein comprises a hidden amino acid combinatorial code that may well be responsible for its ability to develop novel functions while maintaining an optimized folding ability. The present review points to a complex model of evolution of protein moonlighting.

Dynamic Complexes in the Chaperonin-Mediated Protein Folding Cycle

“…How this occurs is still not completely understood and is the topic of much debate (Jewett and Shea, 2010), however, accumulating evidence suggests that in the case of misfolded proteins, the chaperonin exerts an unfoldase action on the protein, overcoming the free energy barrier (Todd et al, 1996; Walter et al, 1996; Finka et al, 2016). In addition, to the major protein-folding activities, moonlighting functions were also reported for plant and various bacterial systems harboring multiple chaperonin homologs (Lund, 2009; Henderson et al, 2013; Vitlin Gruber et al, 2013; Fares, 2014). The most widely studied prototype at the mechanistic level is the GroEL chaperonin of Escherichia coli .…”

Gene duplication and the evolution of moonlighting proteins

“…As discussed above, the tradeoffs between the origin of functional novelty and the maintenance of an ancestral activity may be overcome by the presence of duplicated genes, where loss-of-function mutations in one copy may be compensated by the paralog. However, the ancestral function is expected to be fully or partially conserved under at least two scenarios whereby both gene copies are rendered essential: selection for gene-dosage amplification ( Kondrashov and Kondrashov, 2006 ; Katju and Bergthorsson, 2013 ) or incomplete subfunctionalization ( Force et al, 1999 ; Lynch and Force, 2000 ; Fares, 2014 ). We define incomplete subfunctionalization as the phenomenon where, after duplication, a certain degree of functional overlap is retained between the paralogs.…”

Engineered Functional Redundancy Relaxes Selective Constraints upon Endogenous Genes in Viral RNA Genomes

“…On the one hand, functional redundancy may be the raw material for natural selection to evolve new functions ( Kondrashov et al. 2002 ) or to evolve moonlighting proteins with overlapping yet suboptimal activities ( Lynch and Force 2000 ; Fares 2014 ; Espinosa-Cantú et al. 2015 ).…”

“…2018 ): mediator in vector transmission, RSS, cell-to-cell movement, and cysteine protease. It has been proposed that multifunctionality conflicts with optimization of every function ( Guillaume and Otto 2012 ; Fares 2014 ) and therefore a tradeoff between all these functions is expected. Engineered functional redundancy relaxes these evolutionary constraints and allows multifunctional proteins to optimize the functions that are not being provided in cis , in our case the RSS.…”