What happens when proteins are defective?
Danish researchers have linked changes in DNA to defects in proteins. This is a way to understand precisely how tiny variations in the body’s DNA can result in diseases such as cancer, Alzheimer’s disease, cystic fibrosis and phenylketonuria.
The explosive growth in the access to DNA analysis and the number of people who have had their genome sequenced enable researchers to link ever more diseases to small variations in DNA. These tiny changes in our hereditary material can result in various genetic disorders such as cystic fibrosis or cancer with a strong hereditary component.
Nevertheless, understanding how a single variation in one gene can result in a specific disease requires knowing which protein the gene expresses and how specifically the variation affects the way the protein functions so that the disease can develop.
This crucial link between genes and disease is mostly a black box, but now Danish researchers have begun to shine a light into this murky area, paving the way for many major medical breakthroughs.
“Things often go wrong when genetic variations cause proteins to change. But if we can identify the precise changes in the proteins, we hope to be able to correct or alleviate some of them and thereby prevent the development of various diseases with a hereditary component. We cannot yet alter the genes, but we may well be able to do something about dysfunctional proteins by understanding what goes wrong,” explains the researcher behind the studies, Kresten Lindorff-Larsen, Professor, Linderstrøm-Lang Center for Protein Science, Department of Biology, University of Copenhagen.
Kresten Lindorff-Larsen and colleague Rasmus Hartmann-Petersen recently published a review article in Trends in Biochemical Sciences, in which they examined the current situation of the research field and the way forward.
How variations lead to disease
The backbone of Kresten Lindorff-Larsen’s research is understanding how genes create functional proteins, and how these proteins carry out biological functions.
Every cell in our body contains numerous tiny biological machines whose sole function is to scan our DNA for genes that can be used as blueprints to make proteins.
Many molecular machines are involved in this process. Some translate DNA into proteins, and others prevent them from clumping together so they instead have the right structure that enables them to function.
A third group of machines comprises a protein quality control system, checking all the proteins and removing the incorrectly folded proteins that otherwise do not function as they should.
When the body functions like a well-oiled machine, it produces only correct proteins that can each carry out their function to maintain the health of the organism.
Understanding the body’s waste removers
Many diseases can thus also be linked to defects in one or several steps in this process from gene to functional protein.
Variations in the DNA may arise, resulting in changes in the protein so that, for example, it does not form the correct three-dimensional structure.
Another possibility is that the machines that help prevent the proteins from misfolding do not function properly.
A third scenario is that the protein quality control system – the molecular waste removers – does not work, and the resulting dysfunctional proteins are not removed and degraded and can rampage throughout the system.
“One aim of our research is to understand how this protein quality control system functions and what happens when it does not. My group uses computer models of proteins to describe how proteins fold. We then compare the results with experiments from Rasmus Hartmann-Petersen’s laboratory,” explains Kresten Lindorff-Larsen.
Predicting the risk of disease
A key goal of Kresten Lindorff-Larsen’s research is to be able to predict how a variation in one gene influences the function of one protein and how this in turn influences the development of different diseases.
As researchers learn more and more about the human genome, an enormous database of knowledge has become available to researchers such as Kresten Lindorff-Larsen.
This database of knowledge is a gold mine, but researchers need to find the right tools to explore it. If they can achieve this, they may be able to predict a person’s genetic risk of disease and then treat a disease before the person actually becomes a patient.
“The idea is that sequencing a person’s genome will enable us to determine which genes have variations and then predict how these might affect the folding and stability of proteins. If the cell’s quality control system detects incorrectly folded proteins, they are removed and degraded and cannot fulfil their function. If we can predict how this happens, we may be able to understand the risk of developing specific diseases. We want to understand the mechanisms behind these effects so we can fix the problem rather than simply determine that genes are linked with diseases,” says Kresten Lindorff-Larsen.
The protein quality control system causes cystic fibrosis
The protein quality control system the cells use to differentiate between correctly and incorrectly folded proteins is an important element of the whole production chain from gene to protein. Molecular chaperones that both help the proteins in not misfolding and assist in removing aberrant proteins are an important part of this system.
The protein quality control system and the chaperones can contribute to a person becoming ill, both when they function correctly and when they do not.
For example, in cystic fibrosis, a simple change in the DNA in one gene causes one protein to misfold. Although this is only a tiny defect in the protein, the protein quality control system removes it and the person becomes ill because the body needs to use the protein in the membranes of the cells in the lungs.
The interesting aspect is that, if the cell does not remove and degrade the protein, for example by tricking the protein quality control system, the person will not become ill because the protein can actually function somewhat even though it is misfolded.
“We really want to understand how cells recognize the misfolded proteins. We have known about the basic components for many years, but the molecular details are still unknown. We want to understand the mechanisms in diseases such as cystic fibrosis that result in the removal and degradation of this specific protein. If we can achieve this, we might also be able to inhibit the process so that, even if a person with one variation in one gene is predisposed to developing a disease, the protein will not be removed anyway, and the person will not become ill,” explains Kresten Lindorff-Larsen.
Found the mechanism behind a known childhood disease
The research by Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen has improved understanding of other disease mechanisms, including phenylketonuria (PKU), a hereditary disease for which all newborn babies are screened using a blood sample taken through a heel prick.
Phenylketonuria is caused by the lack of a specific enzyme, and the research by Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen has shown how many of the disease-inducing variations in one gene can result in the enzyme being removed by the cellular waste removers.
“We mapped the specific molecular mechanisms that we suggest could be the cause of many cases of phenylketonuria. Now the task is to produce medicine that can stabilize the enzyme to prevent the cell from degrading and removing it. In the long term, we would like to find other hereditary diseases with the same mechanism and thus be able to offer better diagnostic opportunities and a new approach to developing treatments,” concludes Kresten Lindorff-Larsen.
“Biophysical and Mechanistic Models for Disease-Causing Protein Variants” has been published in Trends in Biochemical Sciences. The Novo Nordisk Foundation awarded grants to Kresten Lindorff-Larsen for the projects Studies of Functional Protein Dynamics and Protein Optimization (POP) and a grant to Rasmus Hartmann-Petersen for the project How Mutations Affect Protein Stability in a Hereditary Disease.