Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts

Abstract

All archaea have a chaperonin of Group II (thermosome) in their cytoplasm and some have also a chaperonin of Group I (GroEL; Cpn60; Hsp60). Conversely, all bacteria have GroEL, some in various copies, but only a few have, in addition, a chaperonin (tentatively designated Group III chaperonin) very similar to that occurring in all archaea, i.e., the thermosome subunit, and in the cytosol of eukaryotic cells, named CCT. Thus, nature offers a range of prokaryotic organisms that are potentially useful as experimental models to study the human CCT and its abnormalities. This is important because many diseases, the chaperonopathies, have been identified in which abnormal chaperones, including mutant CCT, are determinant etiologic-pathogenic factors and, therefore, research is needed to elucidate their pathologic features at the molecular level. Such research should lead to the clarification of the molecular mechanisms underlying the pathologic lesions observed in the tissues and organs of patients with chaperonopathies. Information on these key issues is necessary to make progress in diagnosis and treatment. Some of the archaeal organisms as well as some of the bacterial models suitable for studying molecular aspects pertinent to human mutant chaperones are discussed here, focusing on CCT. Results obtained with the archaeon Pyrococcus furiosus model to investigate the impact of a pathogenic CCT5 mutation on molecular properties and chaperoning functions are reviewed. The pathogenic mutation examined weakens the ability of the chaperonin subunit to form stable hexadecamers and as a consequence, the chaperoning functions of the complex are impaired. The future prospect is to find means for stabilizing the hexadecamer, which should lead to a recovering of chaperone function and the improving of lesions and clinical condition.

Systematic Analysis of Mouse Genome Reveals Distinct Evolutionary and Functional Properties Among Circadian and Ultradian Genes

“…Interestingly, some of the oscillating genes comprised in the 12-h periodicity subset ( Hspa1b , Hspa5, Hspa13, Dnajb1 , Dnaja4 , Dnajb9 ) encode heat shock proteins (HSP). HSP work as molecular chaperones to avert the formation of anomalous protein aggregates and support proteins in the acquisition of their native structures, enriching an ancient signaling pathway activated by abrupt temperature increase (heat stress) harming vital cellular structures and obstructing crucial functions ( Carra et al, 2017 ; Conway de Macario et al, 2017 ). Moreover, UPR activity fluctuates with ultradian pattern in mouse liver cells and especially in the endoplasmic reticulum.…”

Structural and mechanistic characterization of an archaeal-like chaperonin from a thermophilic bacterium

“…The γ-phosphate is further stabilized by Arg155 (Supplementary Fig. 5a ) which is conserved in Group III CPNs 30 (Supplementary Fig. 6a ).…”

The chaperonin GroESL facilitates Caulobacter crescentus cell division by supporting the function of the actin homologue FtsA

“…Chaperonins are highly conserved folding machines that provide essential protein folding across all kingdoms of life. Critical functions of chaperonins range from helping bacteria to build peptidoglycan (47) to supporting chloroplast and mitochondrial function in eukaryotes (60,61), and information from prokaryotic systems has helped to inform exploration of human chaperonins (62). In this present work we expand on how chaperonin function is integrated into bacterial physiology by exploring GroESL function in the alphaproteobacterium Caulobacter crescentus.…”