NMR IS UNRAVELING THE SECRETS OF DISORDERED PROTEINS

Approximately one third of proteins in the human proteome do not adopt stably-folded, globular structures and are instead intrinsically disordered. Also referred to as the “dark proteome,” very little is known about the molecular conformation of these intrinsically disordered proteins (IDPs). However, it is known that disordered proteins are hugely important to cellular function, playing a significant role in cell signaling networks and the control of cellular regulation.

In an interview, Professor Peter Wright from the Department of Integrative Structural and Computational Biology at The Scripps Research Institute discussed some of the breakthroughs his team are making in understanding IDPs, their conformational ensembles and their biological functions.

He explains that when IDPs are in the free-state and not bound to targets, they adopt ensembles of structure; but when they do interact with a target, they often also form dynamically disordered complexes. Since IDPs do not possess unique structures, traditional structural biology methods such as crystallography cannot be used to study them. Wright refers to NMR as the only tool that can be used to investigate the complex and dynamic interactions of IDPs.

“The ability to characterize dynamic proteins, to map conformational ensembles, to follow post translational modifications in real time, and to determine the structure and dynamics of IDP complexes is what makes NMR such a powerful tool,” he explains. Much of the complexity of the signaling pathways in a cell comes from disordered proteins and the post translational modifications that they undergo. Therefore, the more that can be learnt about how IDPs function and their role in signaling and disease, the greater the likelihood of new possibilities opening up for the design of therapeutics.

Currently, Wright and his colleagues at Scripps are particularly interested in DNA tumor viruses such as the human papilloma virus, which causes cervical cancer. They are trying to understand how the IDPs produced by HPV and other DNA tumor viruses interact with cellular targets and compete with cellular IDPs to hijack cellular regulatory networks. These viruses hijack the host cell cycle by using their own disordered protein regions to mimic cellular IDPs.

Wright says there is an important lesson to be learned here because understanding how viral IDPs function in the cell could guide the design of molecules that will disrupt cellular pathways and treat disease, whether they be viral diseases or other diseases.

“We should be able to do the same thing with drugs, by designing small molecules or peptide-like molecules that target the cellular machinery in the same way that viral IDPs do,” says Wright, who believes this is something that could have an enormous impact on medicine and biomedical research in the long term.