Molecular chaperones

Chaperones are unique remodeling proteins that participate in a great number of intracellular processes and are involved in the correction of protein structure, the prevention of the aggregation of misfolded proteins, the destruction of protein aggregates, and also the unfolding of native protein targets for their translocation across a membrane. In addition to this, chaperones assist in the dismantling of active oligomers into inactive unfolded monomers for their subsequent proteolytic degradation and the assembly of folded subunits into protein assemblies and specific complexes. Data on the structure and functioning of molecular chaperones from five basic families are summarized in the review.     

Bacterial secretion chaperones

Many Gram-negative bacteria are able to invade hosts by translocation of effectors directly into target cells in processes usually mediated by two very complex secretion systems (SSs), named type III (T3) and type IV (T4) SSs. These syringe-needle injection devices work with intervention of specialized secretion chaperones that, unlike traditional molecular chaperones, do not assist in protein folding and are not energized by ATP. Controversy still surrounds secretion chaperones primary role, but we can say that these chaperones act as: (i) bodyguards to prevent premature aggregation, or as (ii) pilots to direct substrate secretion through the correct secretion system. This family of chaperones does not share primary structure similarity but amazingly equal 3D folds. This mini review has the intent to present updated structural and functional data for several important secretion chaperones, either alone or in complex with their cognate substrates, as well to report on the common features and roles of T3, T4 and flagellar chaperones.     

Plant copper chaperones

Copper chaperones, soluble copper-binding proteins, are essential for ensuring proper distribution of copper to cellular compartments and to proteins requiring copper prosthetic groups. They are found in all eukaryotic organisms. Orthologues of the three copper chaperones characterized in yeast, ATX1, CCS and COX17, are present in Arabidopsis thaliana. Plants are faced with unique challenges to maintain metal homoeostasis, and thus their copper chaperones have evolved by diversifying and gaining additional functions. In this paper we present our current knowledge of copper chaperones in A. thaliana based on the information available from the complete sequence of its genome.     

Discovery of molecular chaperones

No Abstract Available     

Histone transfer among chaperones

The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.     

Antibodies as specific chaperones

Protein folding is often accompanied by formation of non-native conformations leading to protein aggregation. A number of reports indicate that antibodies can facilitate folding and prevent aggregation of protein antigens. The influence of antibodies on folding is strictly antigen specific. Chaperone-like antibody activity may be due to the stabilization of native antigen conformations or folding transition states, or screening of aggregating hydrophobic surfaces. Taking advantage of chaperone-like activity of antibodies for immunotherapy may prove to be a promising approach to the treatment of Alzheimers and prion-related diseases. Antibody-assisted folding may enhance renaturation of recombinant proteins from inclusion bodies.Translated from Biokhimiya, Vol. 69, No. 11, 2004, pp. 1515–1521.Original Russian Text Copyright © 2004 by Ermolenko, Zherdev, Dzantiev.     

Protein folding assisted by chaperones

Molecular chaperones are one of the most important cell defense mechanisms against protein aggregation and misfolding. These specialized proteins bind non-native states of other proteins and assist them in reaching a correctly folded and functional conformation. Chaperones also participate in protein translocation by membranes, in the stabilization of unstable protein conformers and regulatory factors, in the delivery of substrates for proteolysis and in the recovery of proteins from aggregates.     

Non-iminosugar glucocerebrosidase small molecule chaperones

Small molecule chaperones are a promising therapeutic approach for the Lysosomal Storage Disorders (LSDs). Here, we report the discovery of a new series of non-iminosugar glucocerebrosidase inhibitors with chaperone capacity, and describe their structure activity relationship (SAR), selectivity, cell activity phamacokinetics.     

Polyglutamine diseases and molecular chaperones

The polyglutamine diseases, a group of diseases currently thought to consist of nine inherited neurodegenerative diseases, are caused by the expansion of unstable CAG trinucleotide repeats that code for polyglutamine tracts in the responsible genes. These diseases are now recognized as being of a type with conformationally abnormal or amyloid-related proteins, and thus are called 'conformational diseases'. Recently, many studies using cell cultures and model organisms have suggested that the two major machineries for protein quality control (the molecular chaperone and the protein degradation machineries) play important roles in the pathogenesis of the polyglutamine diseases. Interestingly, molecular chaperones have been shown to behave in totally different ways in these studies, namely in suppressing as well as enhancing neurodegeneration or cell death. These apparently opposite actions of molecular chaperones suggest that a certain balance between the activities of molecular chaperones and the expression level of polyglutamine is an important determinant of the pathogenesis. In this review, we summarize recent findings on such ambiguous effects of molecular chaperones on polyglutamine diseases, and discuss possible mechanisms by which molecular chaperones, especially VCP, are involved in the pathogenesis.     

The story of stolen chaperones

Prions are self-seeding alternate protein conformations. Most yeast prions contain glutamine/asparagine (Q/N)-rich domains that promote the formation of amyloid-like prion aggregates. Chaperones, including Hsp104 and Sis1, are required to continually break these aggregates into smaller “seeds.” Decreasing aggregate size and increasing the number of growing aggregate ends facilitates both aggregate transmission and growth. Our previous work showed that overexpression of 11 proteins with Q/N-rich domains facilitates the de novo aggregation of Sup35 into the [PSI⁺] prion, presumably by a cross-seeding mechanism. We now discuss our recent paper, in which we showed that overexpression of most of these same 11 Q/N-rich proteins, including Pin4C and Cyc8, destabilized pre-existing Q/N rich prions. Overexpression of both Pin4C and Cyc8 caused [PSI⁺] aggregates to enlarge. This is incompatible with a previously proposed “capping” model where the overexpressed Q/N-rich protein poisons, or “caps,” the growing aggregate ends. Rather the data match what is expected of a reduction in prion severing by chaperones. Indeed, while Pin4C overexpression does not alter chaperone levels, Pin4C aggregates sequester chaperones away from the prion aggregates. Cyc8 overexpression cures [PSI⁺] by inducing an increase in Hsp104 levels, as excess Hsp104 binds to [PSI⁺] aggregates in a way that blocks their shearing.     

Slow-wave sleep and molecular chaperones

Since long ago, one of the most vital issues mankind is concerned about is why spending almost one-third of human lives for sleep. This review addresses the major function of slow-wave sleep (SWS) and molecular mechanisms of its regulation. The main conclusions are presented below as the following generalizations and hypotheses. 1. SWS performs an energy-conserving function which developed parallel to the evolution of tachimetabolism and endothermy/homoiothermy. 2. Most significant reduction in the brain energy demands during deep SWS, characterized by increased EEG delta power, creates optimal conditions for the enhancement of anabolic processes and actualization of the major biological function of sleep—accelerating protein synthesis in the brain. 3. Conditions of paradoxical sleep (PS) as an “archeowakefulness”, containing the elements of endogenous stress, seem acceptable for chaperone expression required to fix misfolded proteins synthesized de novo during deep SWS. 4. Close integration of the HSP70 and HSP40 molecular systems, contained in the sleep center of the preoptic area of the hypothalamus, and their compensatory interrelationship contribute significantly to the maintenance of sleep homeostasis and implementation of its functions under non-stress conditions and during a long-term chaperone deficiency intrinsic to ageing and varied neuropathologies. 5. Cyclic changes in the protein synthesis rate (during deep SWS) and HSP70 chaperone expression (during wakefulness and, probably, PS), which occur on a daily basis throughout the entire lifetime, are critical for all vital functions of homeothermic organisms, including recovery of the nervous system structure and functions.