Keep calm, the chaperones are on!


The original nano-machines

I was quite excited to hear the announcement that the 2016 Nobel Prize in Chemistry was awarded to a group of 3 European scientists for developing “nano-machines,” a technological breakthrough which crafted the path for the world’s first smart materials. Sir Fraser Stoddart, Bernard Feringa and Jean-Pierre Sauvage developed the world´s smallest machines, creating synthetic molecules which could function similarly to living cells in terms of carrying out a cell’s physiological functions. As impressive an accomplishment as it is for humans to mimic natural molecules, equally fascinating are the naturally occurring nano-machines that are already present inside our cells, guiding protein folding and quality control. These nano-machines are called chaperones. What impact do they have on health, and why should we study them?

Before we dive deeper into chaperones, let’s quickly go through the protein folding process. It’s very important for a protein to achieve its 3-dimensional conformation during the process of folding so that it can perform its required function inside a crowded cellular environment. The process of protein folding is associated with different cell cycle steps, cell growth and differentiation (1). The pioneering work of Anfinsen, which led to him being awarded the Nobel Prize for Chemistry in 1972, showed that the information needed for a protein to fold into its tertiary structure was encoded in its amino acid sequence (2). The final structure is completed by the association of all the side chains in a densely packed arrangement, with water excluded from the protein`s core (3). Mutations that cause changes in the amino acid sequence may induce conformational errors leading to protein misfolding. As a result, the function of a protein may be compromised, or it could have a toxic gain of function causing protein-folding diseases. Protein-folding errors are associated with a number of different diseases such as neurodegenerative diseases (including Alzheimer’s and Parkinson’s disease), cystic fibrosis and type II diabetes (1). However, the cell is equipped with a number of strategies to combat protein misfolding to promote the normal functioning of cellular activities.

Ensuring proper folding in a crowded space

The cell is probably one of the most crowded places imaginable. To ensure proper protein folding, it employs different protein quality systems in order to get rid of harmful or lethal gene products generated due to mutations affecting amino acid sequences. The role of these protein quality control systems is to recognize and degrade faulty client proteins. The folding status of a polypeptide chain is detected by molecular chaperones, which assist a protein in folding or triage a misfolded client for degradation. Laskey was the first to report about molecular chaperones when he observed that nucleoplasmin, an acidic protein, assisted nucleosome formation by the prevention of histone aggregation (4). Some years later, H. Pelham proposed a group of proteins that help polypeptide chains fold properly and reach their native conformation. Chaperones ensure proper folding of proteins by binding polypeptide chains which are unfolded during the protein folding process, thus preventing their misfolding and aggregation (5).

Chaperones: roles in disease and therapeutic development?

  1. John Ellis in 1993 defined chaperones as “proteins that assist the non-covalent folding or unfolding and the assembly or disassembly of other macromolecular structures, but do not occur in these structures when the structures are performing their normal biological functions having completed the processes of folding and/or assembly” (6). Molecular chaperones, apart from the prevention of misfolding of proteins, are also associated with the recovery of misfolded and aggregated proteins, needing energy in the form of ATP to carry out their function. GroEL/GroES bacterial chaperone machinery belonging to the chaperonin family is an example of this (7). Molecular chaperones are present in cells in different structurally distinct families, which are highly expressed under stress conditions such as heat, oxidative stress or exposure to heavy metal. For this reason, “heat shock protein (Hsp)” has become a synonym for molecular chaperones (8).

Chaperones have been reported to ameliorate the symptoms of various diseases associated with protein aggregation. When chaperone protein expression was induced in models for Parkinson’s and Huntington’s diseases, for example, it resulted in the reduction of neural degeneration. Heat shock proteins are produced in high volumes if there is a heat shock response, which is triggered through the transcription factor heat shock factor-1 (HSF-1) and the heat shock element (HSE), resulting in gene upregulation.

The molecular chaperones Hsp70 and Hsp90 play a central role in protein folding and act in cooperation with various cochaperones that support folding or degradation of a client protein. Heat shock proteins are grouped into 6 protein families on the basis of their molecular weights: Hsp110, Hsp100, Hsp90, Hsp70, Hsp60 and small heat shock proteins (sHSP). How would you profile the expression of key genes that regulate protein folding? There are 2 major approaches: PCR or NGS.

PCR-based approach: Learn more about the RT2 Profiler PCR Array containing HSP90 (81 to 99 kD), HSP70 (65 to 80 kD), HSP60 (55 to 64 kD), HSP40 (35 to 54 kD), small HSPs (=34 kD) and other chaperone cofactors/cochaperones which are directly linked to the UPR unfolded protein response, misfolded protein response or simply involved in protein folding in general.  Using real-time PCR, you can easily and reliably analyze expression of a focused panel of heat shock proteins and chaperones with this array.

NGS-based approach: Traditional RNA sequencing methods suffer from PCR duplication and amplification bias, resulting in inaccurate gene expression analysis. By introducing molecular barcodes before any amplification takes place, QIAseq Targeted RNA Panels are able to eliminate this issue to deliver accurate and digital quantification of genes.

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What do you think about the future of molecular chaperones in translational research and development of therapies for diseases related to protein misfolding? Let us know in the comments!



  1. 1. Radford, S.E. and Dobson, C.M. (1999) From computer simulations to human disease: emerging themes in protein folding. Cell 97, 291.
  2. 2. Anfinsen, C.B. (1973) Principles that govern the folding of protein chains. Science 181, 223.
  3. 3. Fersht, A.R. (2000) Transition-state structure as a unifying basis in protein-folding mechanisms: contact order, chain topology, stability, and the extended nucleus mechanism. Proc. Natl. Acad. Sci. USA 97, 1525.
  4. 4. Laskey, R.A., Honda, B.M., Mills, A.D., Finch, J.T. (1978) Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275, 416.
  5. 5. Pelham, H.R. (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46, 959.
  6. 6. Ellis, R.J. (1993) The general concept of molecular chaperones. Philos.Trans. R. Soc. Lond. B. Biol. Sci. 339, 257.
  7. 7. Bukau, B. and Horwich, A.L. (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92, 351.
  8. 8. Ellis, J. (1987) Proteins as molecular chaperones. Nature 328, 378.
Vishwadeepak Tripathi

Vishwadeepak Tripathi, PhD is a Global Market Manager at QIAGEN. He received his PhD in biochemistry at the Faculty of Medicine from Ruhr-University Bochum, Germany. Dr. Tripathi studied the role of chaperones and co-chaperones in protein folding and quality control and authored a number of scientific publications. He was also at RIKEN Institute in Japan where he studied the pathogenesis of Huntington's disease in cellular and mice models. He is currently interested in biomarker research, NGS and neurodegeneration.

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