Chaperones
Chaperones are proteins that are involved in the folding and unfolding of other macromolecules. They exists both in prokaryotes and eukaryotes. Some chaperones are constitutively expressed in the system where as other chaperones are expressed only in response to an external stimulus or stress such as heat and therefore they are referred to as heat shock proteins. They are classified based on their structure, size, molecular weight and function in to several classes such as Hsp40s, Hsp60sChaperonin, Hsp70s, Hsp90s, Hsp100 and small heat shock proteins (alpha)-crystallin proteins. Molecular chaperones work cooperatively on the nascent polypeptide chains in the cyotplasm resulting in to folding pathways, many of them are evolutionarily conserved[1]. FunctionChaperones bind to the newly synthesized and unfolded proteins helping them acquire their properly folded 3D structure [2] Besides, chaperones help in targeting the native proteins to their respective organelles [3][4] The first identified chaperones were the histone chaperones that are continously involved in histone metabolism thus regulating genome function, stability and identity[5]. Many protozoan parasites such as Plasmodium falciparum requires these proteins for cytoprotection [6] [7]Chaperones actively participate in the maintenance of proteome integrity, and protein homeostasis (proteostasis) which requires a syncrhonization in various chaperones tuning the process [8]. DiseaseChaperones are instrumental in protein folding processes. Any alteration in this process leads to protein aggregation and formation of inclusion bodies. Proteostasis also leads to protein misfolding resulting in various diseases such as Alzheimer[9],Cytosolic neurofibrillatory tangles,Parkinson[10],Familial amyotrophic lateral sclerosis, Huntington, Spinocerebellar ataxia 1, 2, 3, disease, Spinobulbar muscular atrophy and ageing[11]. RelevanceModulation of chaperones expression is the new therapeutic approach for neurodegenerative and other disease arising from protein misfolding. There is a distinct network of chaperones and co chaperones that either directly influences the substrate proteins or in association with the protein degradation pathways such as the ubiquitin-proteasome-system or autophagy, results in the removal of completely misfolded and pathogenic proteins[12]. Structural highlightsStructurally, Hsp70 have a N-terminal ATPase domain followed by a substrate binding domain with elongated C-terminal. These domains allosterically regulate the hsp70 functioning. 4JN4 is a representative example of a chaperone system in complex with ADP. In the 2D figure given below, panel A indicates the various folded (green) and unfolded (red)regions in Hsp70. Panel B shows the structural organization of Hsp 70 indicating its various domains. ATP binding and hydrolysis regulates the affinity for substrate proteins which thereafter enhances ATP hydrolysis [13].
| |||||||||||
