NYU Department of Chemistry Professor Nate Traaseth and collaborators from the NYU School of Medicine (Moosa Mohammadi and Thomas Neubert labs) have investigated how disease causing mutations affect kinase structure and activity. Their findings reveal important regions within the kinase domain that could be targeted by inhibitors to prevent the harmful effects of disease-causing mutations. The study, entitled "Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases," appears in eLife [2017;6:e21137]. First authors are Huaibin Chen and NYU Chemistry graduate student Billy Marsiglia. To read the article, click the title.
eLife Digest's Abstract: Many growth factors and hormones instruct cells to act in particular ways – for example, to divide, specialize or migrate – by binding to proteins called receptor tyrosine kinases on the surface of the cell. Receptor tyrosine kinases comprise a region that binds to the signaling molecules outside the cell (the receptor domain) and a region that interacts with and modifies other proteins within the cell (the kinase domain). When a growth factor or hormone binds to the receptor domain, the receptor domains of two identical receptor tyrosine kinases form a dimeric complex, bringing the kinase domains close together so that they can activate each other. This activation initiates a long chain of protein-protein interactions that leads to a cellular response.
Some mutations that occur in the kinase domain cause the kinase to frequently sample the activated state without needing to bind to a signaling molecule. This can lead to cancer or growth disorders. It is not known how these mutations allow the kinase domain to bypass the control mechanisms that prevent it from activating at the wrong time.
Fibroblast growth factor (FGF) receptor is a receptor tyrosine kinase in which many disease-causing mutations have been identified in the kinase domain. Chen, Marsiglia et al. have now used the human form of the FGF receptor to investigate how some of these mutations affect kinase structure and activity. The structures of normal and mutant forms of the FGF receptor were determined using X-ray crystallography and nuclear magnetic resonance spectroscopy. Combining these results with activity data from the diseased receptors revealed four key interdependent sites in the protein that play essential roles in maintaining the receptors in an inhibited state. Disease-causing mutations are generally located in these sites, and take advantage of their interdependence to make the kinase active more frequently, even when the receptor domain is not bound to a signaling molecule.
Chen, Marsiglia et al. suggest that these sites may act in the same way in other receptor tyrosine kinases, as these proteins have many similarities in their structures. The findings reveal important regions within the kinase domain that could be targeted by inhibitors to prevent the harmful effects of disease-causing mutations. Future studies will be needed to understand in more detail how interactions between the key sites change the activity of the kinases.
Research conducted in the NYU Department of Chemistry was supported by the National Institutes of Health. This research was additionally supported with grants from NIDCR, NINDS, NIAID, DOE and NYSTAR, and by these organizations: National Synchrotron Light Source, The New York Structural Biology Consortium and Brookhaven National Laboratory.