Professor Hoogenraad says that the folding of proteins to their final, functional 3-D shape is driven by thermodynamic forces.Ĭells have a watery environment, yet many of the amino acids in a protein are "water-hating" (hydrophobic) - the protein solves this problem by hiding its hydrophobic amino acids in its interior, so only the "water-loving" (hydrophilic) amino acids exposed to interact with the watery cytosol. The discovery of molecular chaperones has forced biochemists to revise their views about how proteins form and behave. The whole complex binds to a mitochondrial import receptor and the protein then travels through a pore where it then undergoes folding," he said. "HSP70 wraps around the protein and prevents it folding. Yet his "unfoldase" proved to be a ghost, for the real answer to the problem of protein shape and translocation across membranes lies in the association of proteins with molecular chaperones from the instant that the protein is made.ĭHFR did not travel alone - Professor Hoogenraad says it is now clear the protein molecules are escorted to their mitochondrial destination by molecular chaperones, specifically a chaperone called heat-shock protein 70 (HSP70). Indeed, when he treated his cell culture with a compound to lock DHFR molecules permanently into their 3-D shape, they were prevented from finishing up inside mitochondria. Initially he suspected some enzyme - an "unfoldase" - had unravelled the protein, making it slender enough to thread through the pore. In 1986, Swiss Biochemist Dr Geoff Schatz, from the Biocentre in Basel, took a gene for a protein called DHFR and grafted in a DNA sequence that re-addressed its protein to a new cellular location: instead of floating in the watery cytosol of the cell's interior, it ended up inside the mitochondria.ĭHFR is a bulky protein, and Schatz was challenged to explain how it had squeezed itself through a tiny pore in the mitochondrial membrane. However, within the crowded environment of the cell, it is now clear they need help from molecular chaperones. It is a central dogma in biochemistry that the amino-acid sequence contains all the necessary information for a protein to fold spontaneously into its final form.
#Roles of chaperone proteins in bse code
The basic role of molecular chaperones is to assist proteins to fold into correct shapes, then keep them that way.Ī protein starts out as a chain of amino acids, whose sequence is specified by the DNA code of a gene. "Understanding how they work has enormous implications for our understanding of normal cell function, and what happens when things go wrong".Ī protein's three dimensional shape, says Professor Hoogenraad, is as vital to its function as its underlying amino-acid chemistry. "The ultimate function of all living cells depends on proteins, but molecular chaperones are the overlords of the system", says Professor Hoogenraad. There is now considerable evidence to suggest that the basic error is not genetic but a problem of protein-folding, and finger of suspicion has been pointed at a remarkable family of molecules called molecular chaperones, which are critically involved in protein folding. Yet heredity can only account for a minority of cases of prion diseases, which means abnormal proteins can arise in the absence of any inherited genetic defect, says Professor Hoogenraad. When a protein misfolds, scientists tend to look for some subtle, inherited mutation in the gene that encodes it. Prions, says Professor Hoogenraad, are basically misfolded proteins that aggregate in brain tissue, killing nerve cells. Professor Hoogenraad, head of the School of Biochemistry, points to a group of brain disorders that cause dementia and death, including Gerstmann-Straussler Schinker syndrome, New Guinea's "laughing disease", kuru, Creutzfeld-Jakob disease and the closely related "mad cow" disease BSE (bovine spongiform encephalopthy).Īll involve an unusual class of infectious agents called prions.
In fact, he says, it has recently become clear that the accumulation of unfolded proteins can kill. Proteins form the machinery of cells and since a protein's function is highly dependent on its 3-D structure, misfolded proteins can be disastrous to a cell.
Life, says Professor Nick Hoogenraad, can pivot on something as simple as the shape of a protein molecule. This report is © the property of the Faculty of Science and Technology at La Trobe University, and is produced here with permission. This is a report of a 1996 interview with Professor Nick Hoogenraad, Chairman of the School of Biochemistry, La Trobe University.
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