In textbook biology, a protein can only function correctly if it adopts a defined three-dimensional conformation. There was a tendency to consider disordered protein segments as the inevitable product of some amino acid combination without any predefined purposes. However, about a third of the human proteome is composed of proteins that have high levels of disorder and dynamically switch between a range of conformations without adopting a defined structure. They are known as intrinsically disordered proteins (IDPs) or the more recently coined (and catchier) "dark proteome."

The significance of IDPs was ignored for years until comparative genomics revealed that they are not randomly distributed. IDPs were found to be enriched in key cellular processes—signaling and regulation. This is true for the unicellular yeast to humans and every organism in between. This functional conservation could simply mean that these particular processes tolerate the disorder of IDPs without there being any positive contribution or a serious disadvantage for evolution to intervene. It could also mean that the conformational plasticity that results from disorder is, in fact, essential for cellular signaling and regulation.

So, to understand the benefits of disorder in proteins, we need to look beyond the structure-function relationship and into the biological systems in which IDPs operate.

Cellular signaling requires a network of interacting proteins. Disorder gives a degree of flexibility that allows IDPs to bind multiple partners, sometimes at once. Some IDPs can even adopt completely unique folds to accommodate each partner. The variations in entropy between the free and bound states of IDPs are large. All this results in a combination of quick but specific associations and dissociations, making IDPs incredibly tuned for signaling.

It may be unsurprising that large multifunctional proteins are enriched in unstructured regions. These so-called hub proteins bind multiple partners to form dynamic complexes that incorporate and transfer information from various signaling pathways. Flexibility also allows greater accessibility for post-translational modification. The same sequence can be readily, reversibly, and quantitatively modified adding an amazing level of complexity and diversity to signaling and regulatory pathways.

But disorder brings it own problems. BRCA1 and p53 mutations are just two examples of how disruption of the physiological functions of disordered segments can have devastating implications for human health. When IDPs assume non-native folds, functional protein interactions are disrupted, both in time and in space. Imagine a severe traffic jam - plus dysfunctional traffic lights. Some IDPs also have a tendency to form higher order structures known as amyloid fibers. These stable aggregates accumulate with age and cause Alzheimer's disease and other human neurodegenerative diseases. There are also the much-vilified prions. Virtually indestructible, alternative conformations of certain disordered proteins that get inherited from mother to daughter cells, effectively spreading like an infection.

But if IDPs were so volatile—one conformational switch away from causing chaos in the cell—then why hasn't evolution found a way to get rid of them? The answer is that evolution found a way to harness IDPs by keeping their concentration and spatial distribution within the cell under very tight control. Thus, the risk of non-functional connections is kept to a minimum. And like always, there's more to the unexpectedness of nature. Controlled disorder can be innovative. And the most exciting roles of IDPs are only just being uncovered.

When we think of intelligent behavior, we imagine organisms with highly evolved nervous systems. In biological terms, intelligence means retaining information from past experiences to respond more efficiently if the same conditions arise in the future. Or quite simply, having a memory. And research shows that intelligence is deeply rooted in our most primitive ancestors, the single-cell primitive ancestors.

Yeast cells can remember previous unsuccessful mating attempts. And IDPs play a role in the molecular mechanisms underlying this primitive memory. Whi3, a protein with disordered regions, is a regulator that inhibits asexual cell division when mating is about to happen. If mating does not occur, then Whi3 assembles into inactive amyloid-like structures, mediated by the disordered segments, in the cytoplasm. Because these structures are stable, the information of previous unsuccessful mating attempts is retained in the cell—i.e., a molecular memory is formed. But they are not transmitted to daughter cells. This is advantageous to the population because the mother cells will retain information from previous states and most likely divide asexually, and the daughter cells are allowed to have their own experiences, ensuring that mating and genetic diversity is kept.

What's extraordinary is that, from the disorder of an IDP, a prion, one of the most stable structures, can arise. And prions are not just accidents waiting to happen.

In our most primitive ancestors, the yeast cells, IDPs can act as environmental sensors. Ethanol and hypoxia are two conditions that yeast cells come across during their natural life cycle. Ethanol triggers the assembly of the transcriptional regulator Mot3 into a prion form and hypoxia triggers the switch back to the soluble form. This reversible switch not only reprograms the cells' metabolism but also their appearance. They transition from free-living to multicellular structures, a kind of primitive tissue. And since prions are inherited, they carry epigenetic responses—changes in gene activity that allow organisms to anticipate and adapt to variations in their environment and you can read more about it here.

Nature, it seems, is good at making order out of disorder. The chaos of IDPs is efficiently harnessed to engineer subcellular compartments. IDPs can form phase separated liquid droplets - dynamic membrane-less compartments containing RNA-protein complexes. These droplets can mature over time via increasing protein-protein interactions creating a gradient of viscosity ranging from liquid, to gel-like to amyloid-like (see more here). We have always looked to nature for inspiration. Can we imagine using IDPs to synthesize drug or nucleic acid-delivering granules?

Yes, we can.