Protein structure theory unfolding

The central dogma of molecular biology, which holds that proteins are globular and well-folded and their structure relates entirely to their function, is being unseated by the growing understanding that many proteins - and in particular those involved in cell signalling and expressed in disease states - are intrinsically disordered.

The emergence of disordered proteins poses challenges to a pharma and biotech industry that is tied to the structure/function model and yet to latch onto disordered proteins as potential drug targets. A growing list of proteins - 600 at the last count - are unable to fold spontaneously into globular, well-defined 3D structures, and are partly or completely disordered.

However, this “hasn’t got through to the textbooks,” Peter Wright, of the Scripps Research Institute in California told the American Association for the Advancement of Science meeting in Washington, DC, last month. Yet, Wright estimates that around 60 per cent of proteins involved in cancer or cell signalling proteins are disordered to some extent. Whereas in the structure equals function view interactions between biological molecules are seen as very specific – like a lock and a key - disordered proteins are often “promiscuous” in their interactions.

Tools for uncovering disorder proteins

Disordered proteins have been overlooked because the routine way of establishing a protein’s structure is to crystallise it first. But this is hard to do if proteins are disordered. Early examples of disordered proteins that came to light, such as casein in milk, were dismissed as oddities.

But in the past 20 years tools such as nuclear magnetic resonance, fluorescence probes and atomic force microscopy, which make it possible to examine proteins without the need to crystallise them first, have led to the identification of many other examples.

“By 1999 there was enough information to see they are pretty common,” Wright said. In the time since then, bioinformatics has become a major tool in uncovering and classifying disordered proteins.

It has also become evident that disordered proteins perform many critical functions and are expressed in a wide range of diseases, including cancer and neurodegenerative diseases. However, said Wright, the association between disordered proteins and disease remains largely unappreciated.

“Frequently [disordered proteins are] central hub proteins in regulatory networks, binding numerous target proteins,” Wright said. “The biologist’s view of a protein/protein interaction is binary: on/off or bound/unbound.” But interactions involving disordered proteins are hugely dynamic and transient, often they compete for the same binding sites, they can bind to multiple targets, and they are channels for cross-talk between signalling pathways.

New potential in drug discovery

The potential that disordered proteins hold for drug discovery can be illustrated by the way in which viruses use disordered proteins to hijack the replication machinery of cells they infect. Disordered proteins are highly abundant in viruses, enabling them to mimic proteins in the host cell. For example, Wright noted, all but one of the proteins produced by one adenovirus he has studied are disordered.

“Viruses have already done an extremely good job of interfering with cell machinery using disordered proteins,” he said. It should be possible to mimic this effect with small molecules or peptides that link up to the cellular machinery in the same way. “So you begin to see it needs a frame shift in the way that pharma thinks, and there are some hints this is beginning to take place.”

In addition, small molecule inhibitors could be developed against disordered proteins themselves. This is an enticing prospect, given the role they play in pathologies including cancer and neurodegenerative diseases.