Proteins in our body have to fold correctly to work properly. Scientists have found a way to shepherd the ones that go awry back to the fold. Prasun Chaudhuri has the story
- Published 20.11.17
These tiny molecules may remind you of a doting mother who guides her baby along the right path and tries her best to remove all obstacles in the child's life. In the parlance of molecular biology, they are called chaperones. They help proteins - the basic building blocks of life - follow the correct course of action and not stray towards complicated disorders or debilitating diseases.
Most proteins in our body are supposed to fold into a well-defined three-dimensional structure in order to perform their functions properly. Inside the hundreds of thousands of cells in our body, there are nearly 20,000 different proteins that serve a diverse set of critical functions.
For example, if our body is attacked by a bacterial infection, proteins known as antibodies bind to the bacteria and help destroy them. Enzymes are proteins that accelerate thousands of chemical reactions that occur in our body including digestion of food. The protein hormone insulin is responsible for the control of blood sugar. Transport proteins move molecules around our bodies; haemoglobin, for instance, transports oxygen through the blood.
"Proper protein function depends on the three-dimensional shape, or folds, of the protein," says Subhasis Halder, a postdoctoral researcher at the department of biological sciences in Columbia University, US. "Proteins may unfold and then collapse into an improper shape or aggregate, leading to severe diseases such as Alzheimer's or Prion."
Haldar, along with a group of co-researchers at the lab of Prof. Julio Fernandez, has been working to develop a novel technique called magnetic tweezers. Tiny magnets attract particles attached to the end of a protein, applying minuscule forces to make the protein unfold when it takes a wrong twist and folds wrongly. "The proteins are unfolded in the presence of molecular chaperones, a special class of proteins. These chaperones bind to unfolded peptides [a smaller protein with a less well-defined structure], ensuring that they return to their correct, functional shape," says Haldar.
The Fernandez lab has been looking specifically at the "trigger factor" chaperone from the bacteria E. coli, a type of bacteria that normally lives in our intestines. Most types of these bugs are harmless and even help keep our digestive tract healthy. Bacteria also need to ensure proper folding of their own proteins, so the most abundant chaperone of E. coli was chosen as a model for studying these interactions.
The process they applied - single molecule technique (SMT) - is required to measure the shape of proteins that are as wide as a thousandth of a human hair and far too small to be seen with a conventional microscope. The novelty of SMT is that at the level of only one molecule, all the proteins are monitored separately to identify properties that would otherwise get lost in the crowd or "average out". Explains Haldar, "Imagine a big flock of birds in the air that appears green. But when it lands, you find half of the birds are blue while the other half, yellow."
In the experiments, microscopic magnetic beads were used to apply minuscule force (about a trillionth of a pound) to a single immunoglobulin protein - a protein produced mainly by plasma cells in the blood to fight disease-causing bacteria and viruses. "The mild force caused the immunoglobulin to unfold, permitting the trigger factor to bind and modulate the folding process," he says. Then the researchers found that in the presence of the trigger factor, the immunoglobulin folded hundreds of times faster than it would have done otherwise. While it was previously known that trigger factor can recognise unfolded substrates and prevent them from misfolding or forming odd aggregates, this great acceleration of folding time had never been seen before. "Alzheimer's and some types of cancer are directly related to protein misfolding. Thus, it could be useful to understand the molecular mechanism of these disorders," says Haldar.
This provides an important insight by demonstrating an assay or diagnostic test that could be used to study the chaperones to fight against protein misfolding in humans and keep the tissues healthy. "There is also a great interest in compounds that inhibit these chaperones as a new strategy for battling cancerous cells and bacterial infections," he adds. The research was published in the journal Nature Communications.
Krishnananda Chattopadhyay, a principal scientist at the Indian Institute of Chemical Biology, Calcutta, thinks this is a significant piece of research. "Previously, using single molecule force spectroscopy techniques (like AFM force spectroscopy), we could monitor a single protein for a few seconds. With this new covalent technology, we could monitor the dynamics of a single protein (for example, unfolding and refolding, formation of intermediates and chemical transformation) for more than a week at biologically relevant force regime. This technique opens a new window to address and solve difficult protein folding questions."
Prof. Md Imtaiyaz Hassan from Jamia Millia Islamia, too, believes this is a landmark work. He says, "Mechanism of molecular chaperones are very complicated. This is a fundamental work showing how the molecular chaperone works under force. This is very important because our proteins are under force in several circumstances, for example when we stretch or run or do any exercise."
Simply put, proteins need a mother figure to chaperone it towards a healthy future. Haldar and his colleagues are trying to ensure that.