Frontiers in Structural Biology. The Hsp90-TPR Domain Interaction

GALIGNIANA MD

Bentham Science Publishers

Año: 2018 p. 280

978-1-68108-616-3

PREFACEFrom a social perspective, the word chaperone refers to a matron who used to accompanyyoung people in public, especially ladies, and supervise them at a social gathering to ensureproper behavior. Similarly, those proteins that assist others in their proper folding andbiological functions are also referred to as chaperones. During the late ?70s, it was coined theterm ?molecular chaperones? to make reference to the ability of nucleoplasmin to prevent theaggregation of histones with DNA during the assembly of nucleosomes. As a consequence,this nomenclature was extended to all proteins able to mediate the post-translational assemblyof protein complexes. Although the primary concept of molecular chaperone was related to itsability to ensure the correct folding of newly synthesized peptides and refolding of stressdenaturedproteins, it should be noted that chaperones are also involved in essential and moresophisticated functions such as promoting the correct assembly of oligomeric complexes. Oneof the most remarkable examples for this special feature is the ability of a particular subfamilyof molecular chaperones, the heat-shock proteins, to assist the proper assembly of steroidreceptors with chaperones and co-chaperones. This important feature permits the binding ofsteroids to activate isoform of the receptor, which functions as a ligand-dependenttranscription factor.The term ?heat-shock protein? stems from the original observation that heat-stress greatlyenhances the production of this particular class of molecular chaperones. This means that allheat-shock proteins are molecular chaperones, but not all molecular chaperones arenecessarily heat-shock proteins. Temperature is not the only stimulus able to induce heatshockproteins. Upon the onset of several environmental types of stress or due to the exposureto damaging and extreme insults, the cells increase dramatically the production of molecularchaperones, which play prominent roles in many of the most basic cellular processes bystabilizing unfolded or misfolded peptides, giving the cell time to repair or re-synthesizedamaged proteins. In addition to commanding the proper folding of a factor exposed to anenvironmental injury, many chaperones are also related to other key functions such as enzymeactivity, cytoskeletal architecture, nuclear organization, protein trafficking, transcriptionalregulation, epigenetic alterations of gene expression and, even more intriguingly, heritablealterations in chromatin state.The biological relevance of molecular chaperones during the modern times was discoveredduring the early 1960s when the Italian scientist Ferruccio Ritossa was studying nucleic acidsynthesis in puffs of Drosophila salivary glands. A colleague accidentally changed thetemperature of the cell incubator and an incredible transcriptional activity of newchromosomal puffs was evidenced. The induction of these proteins is one of the mostimportant manifestations of environmentally induced changes in gene expression.The whole proteome of the cell is successfully maintained thanks to the assistance ofmolecular chaperones. In addition, the subcellular localization, local concentration, andbiological activity of each protein must be strictly regulated in response to both intrinsic andenvironmental stimuli. The recently coined portmanteau word proteostasis describes thisequilibrated state of the healthy proteome balance, whereas the term proteostasis networkrefers to the group of cellular events and factors involved in proteostasis maintenance.Failures of proteostasis regulation are responsible for a number of diseases as well as for thedeleterious consequences of physiologic processes such as ageing. Since molecularchaperones play a key role in the maintenance of this proteostasis network, they becamepotential pharmacological targets to preserve that proteostatic function and to improve thebiology of the cells by enhancing certain activities (or preventing others). In this regard,iseveral endeavors are currently focused in targeting Hsp90 and some of its cochaperones suchas high molecular weight immunophilins and p23. Currently, this is being tested as anexciting alternative for molecular-based therapies, particularly in both malignant andneurodegenerative diseases.In this book entitled Role of molecular chaperones in structural folding, biological functionsand drug interactions of client proteins, several aspects of the biology of these key proteinshave been addressed with the purpose of providing an updated overview of the field. Themajor aim is to present a broad spectrum of the molecular mechanisms of action of severalmolecular chaperones. Understanding these mechanisms will permit to focus on the design ofsmall molecules able to regulate such functions in the complex cellular milieu affecting theproteostasis network in diseases characterized by aberrant protein folding. Above all, I wishto acknowledge the valuable viewpoint of all contributing authors and hope that thisassemblage of perspectives will be a valuable resource for researchers in this and other relatedfields. Also, I hope that the high enthusiasm showed by all our contributors to make thisendeavor possible will be appreciated by the readers. Finally, I must express my greatestthanks to the editorial for the encouraging support to face this endeavor.Mario D. GalignianaLaboratory of Nuclear ReceptorsInstitute of Biology & Experimental MedicineBuenos AiresArgentina