Molecular Chaperones In Biology, medicIne And proteIn Biotechnology

Rhodes Centenary

South African Journal of Science 100, November/December 2004

665

Molecular chaperones in biology, medicine and protein biotechnology
A. Boshoff*, W.S. Nicoll*, F. Hennessy*, M. Ludewig*, S. Daniel*, K.W. Modisakeng*, A. Shonhai*, † C. McNamara*, G. Bradley* and G.L. Blatch*
uration. Molecular chaperones do not contain any steric information for the folding process of asubstrate protein, but play a vital role by guiding proteins along productive protein folding pathways. Chaperones also play central roles in the translocation of proteins across intracellular membranes into organelles, and facilitate the proteolytic degradation of unstable proteins.5 In general, the main molecular chaperones function in a nucleotide-dependent manner, and the release of thesubstrate protein is usually associated with an ATP-coupled conformational change by the chaperone.6 Many chaperones are constitutively expressed (Hsc proteins), while the synthesis of other chaperones (Hsp proteins) increases after a period of stress or the so-called ‘heat shock response’. According to Finkelstein and Strausberg,7 the heat shock response was first described in Drosophila by Ritossa in1962. It is now generally accepted that this response is similar for different types of stress, and is conserved in most organisms. One of the common features of the response is an increased rate of transcription of the genes that encode the inducible heat shock proteins, followed by enhanced synthesis of these proteins.8 Stressful circumstances induce the synthesis of more than 20 heat shockproteins that enable cells to adapt to environmental and metabolic changes and to survive stress conditions.9 Hsps are highly conserved and play similar roles in organisms from bacteria to humans. In eukaryotic cells, heat shock genes include a conserved sequence referred to as the heat shock element (HSE) within the promoter region; the genes are activated by a protein called the heat shock factor(HSF).10 The heat shock response in Escherichia coli is positively controlled at the level of transcription by the heat shock promoter-specific F32 subunit of RNA polymerase, that is a product of the rpoH gene.9,11 There are several families of heat shock or stress proteins, defined on the basis of molecular weight. This review focuses on the functions of the 90-kDa heat shock protein (Hsp90),70-kDa heat shock protein (Hsp70) and 40-kDa heat shock protein (Hsp40) classes of chaperones, highlighting the cooperation between different chaperones to carry out specific functions. The diverse roles of these particular classes of proteins in the life cycle of a protein are outlined in Fig. 1. The terms Hsp40 and Hsp70 are used for the heat shock proteins in eukaryotes, whereas these proteins inbacteria are called DnaJ and DnaK, respectively. In this review we use Hsp40 and Hsp70 as general terms. A number of diseases, such as Alzheimer ’s, have been attributed to the formation of aggregates of protein referred to as amyloid, and the role of molecular chaperones in the development of these diseases is beginning to be understood.12 The implications of heat shock proteins in the control ofdisease pathology and in the survival of pathogens are examined in this review. Recombinant protein production can result in the formation of insoluble inactive aggregates that decrease the yield of active protein.13 Therefore, we also review the targeted use of molecular chaperones for the over-production of recombinant proteins.

Molecular chaperones consist of several highly conservedfamilies of proteins, many of which consist of heat shock proteins. The primary function of molecular chaperones is to facilitate the folding or refolding of proteins, and therefore they play an important role in diverse cellular processes including protein synthesis, protein translocation, and the refolding or degradation of proteins after cell stress. Cells are often exposed to different stressors,...