Patients suffering from a rare disorder called glucose transporter type 1 (Glut1) deficiency suffer from seizures and can develop neurological problems if untreated. The disorder is caused by various defects in one gene that hinders Glut1 protein’s ability to transport glucose from the blood into the brain, but how these defects cause disease has remained poorly understood. A new study offers insight into changes that occur in previously overlooked segments of Glut1 protein that could shed light on disturbances that occur in this and other genetic disorders. The research was done at the Max Delbrück Center for Molecular Medicine (MDC) and published in Cell.
In Glut1 deficiency, and many other genetic diseases, there is a point where the protein’s three-dimensional structure is disrupted, leading to loss of function. However, in one-fifth of all genetic diseases, the protein structure does not appear to be damaged at all. In such cases, according to the scientists, mutations occur in flexible loops in the proteins called ‘intrinsically disordered regions’ that were previously thought to have no function as they lacked defined structure. It is now understood these regions do have functions as they affect cell dynamics and interactions between proteins.
The researchers began their search by looking into which of the cell’s proteins come into contact with mutated intrinsically disordered regions. They did this by recreating 258 flexible proteins in test tubes and adding human cell extracts. This was done with both healthy and disease-related variants.
Using mass spectrometry, the researchers observed that mutated and healthy regions tended to dock onto the same binding partners. However, some of the mutated proteins lost their ability to bind to other proteins, thus disrupting the operation of the cell’s machinery.
In one such case, a mutation in the Glut1protein gene led two leucines to lie next to one another, creating a dileucine motif known to attract proteins that aid the cell in transporting other proteins. This led the authorize to believe that there might be a possibility that the Glut1 protein is not defective in such cases, but instead has ended up in the wrong place. "If the protein itself is not affected but only the transport function, there is a chance that the underlying cause can be treated - not just the symptom," said Katrina Meyer, a doctoral student in lead author Matthias Selbach’s lab.
In cell culture tests, Meyer was able to get glucose uptake to resume by rerouting Glut1 protein in a case in which transportation issues were present. While medications to perform such tasks do not currently exist, they could theoretically be developed. Such medications could have implications beyond Glut1—a database search by the team revealed similar issues in other diseases, including in the protein that triggers cystic fibrosis.
Image: The Glut1 protein molecules (green) appears mainly in the interior of the induced pluripotent stem cells derived from a patient. Image courtesy of Katrina Meyer, MDC.