8/23/2023 0 Comments Molecular chaperone schematic![]() This may lead to undesirable interactions with peptides, nucleic acids and other macromolecules. When proteins are not natively folded, hydrophobic amino acids, which are normally buried in the core of folded globular proteins, may be exposed. These include cytoplasmic (Hsc70/HspA8), endoplasmic reticulum (ER BiP/Grp78/HspA5) and mitochondrial (mtHsp70/Grp75/HspA9) Hsp70s. Further family members have been found in multiple cellular compartments and with tissue specific localizations. These included some family members with high levels of constitutive expression. The first Hsp70 proteins to be identified were strongly induced in response to heat shock e.g. In humans, there are 13 Hsp70 proteins (whilst there are only three in Escherichia coli), plus four related Hsp110 proteins ( Vos et al. The majority of genomes code for multiple members of the Hsp70 molecular chaperone family, with higher organisms processing more Hsp70s. Finally, we also consider whether the Hsp70 machinery may have a role in the processing of G protein-coupled receptors (GPCRs). ![]() Here, we give an overview of the Hsp70 molecular chaperone machinery and then describe examples of specialized Hsc70 functions, concentrating on endocytosis, exocytosis and protein degradation. 2003), that go well beyond steroid receptor processing. In fact, for the Hsc70 chaperone machinery, a very broad range of localized functions have been identified ( Young et al. The paradigm of Hsc70 and Hsp90 chaperone systems functioning throughout the life cycle of steroid receptors clearly illustrates that chaperones do not function solely in the folding of newly translated proteins, but are required for multiple cellular processes. The chaperone system that is responsible for the maturation of steroid receptors, to a conformation that is capable of high-affinity hormone binding, is comprised of Hsc70 (the cytoplasmic cognate Hsp70), Hsp90 and a number of cofactors known as cochaperones ( Pratt & Toft 2003, Prescott & Coetzee 2006, Grad & Picard 2007, Smith & Toft 2008). The best recognized role for chaperones in the context of molecular endocrinology is their essential involvement in the functional maturation of steroid receptors, where it has become clear that receptor folding, maturation, nuclear trafficking and disassembly of transcriptional regulatory complexes are all chaperone dependent ( Freeman & Yamamoto 2002, Prescott & Coetzee 2006, Grad & Picard 2007). To combat the problems of cellular protein folding helper proteins, which function as ‘molecular chaperones’, have evolved. Furthermore, additional detrimental effects may be caused by the aggregation of misfolded polypeptides ( Dobson 2003). Thus, incorrect folding leads to a reduction in levels of functional proteins. Partially folded proteins may have undesirable interactions with other essential cellular molecules. Proteins may not be able to fold fully until their polypeptide chain and/or other subunits are fully synthesized. To become functional and fulfil their cellular roles, the vast majority of proteins must fold into complex three-dimensional shapes.
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