Breaking the Rules

We have known for decades that proteins consist of tens to thousands of amino acids strung together, but it has proven difficult to predict the function of a given protein based on its amino acid sequence. This difficulty rests on the overarching principle that the 3D structure of a protein determines its functionality by specifying with which other proteins and molecules it can interact. Conventional structural biology approaches, likeX-raycrystallography, haveenabledus tofigure out the shapes and interactionsofmany rigidly foldedproteins or their constituent domains. However, sometimes invisible to crystallographers are so-called low-complexity and intrinsically disordered regions of proteins, which often do not form stable and predictable 3D structures in physiological conditions or in the absence of their binding partners. Despite this conformational heterogeneity and flexibility, intrinsically disordered proteins (IDPs) and unstructured stretches of amino acids participate in many essential processes and provide new paradigms for protein-protein interactions. IDPs are generally thought to either conditionally establish secondary structure elements upon binding to their target or remain unfolded and participate in low-affinity, high-avidity dynamic interactions with other proteins. The former case can be exemplified by the formation of an a-helical region in the disordered domain of the transcription factor CREB upon binding to its transcriptional coactivator, CBP/p300 (Sugase et al., 2007). Transient and multivalent interactions are perhaps best illustrated by the core selectivity filter of nuclear pore complexes, where proteins with low-complexity sequence regions dynamically bind and unbind at many sites on the surface of nuclear import or export receptors, which is thought to drive fast directional transport. Indeed, intrinsically disordered regions of proteins mediate many of the multivalent interactions that form the basis of phase-separated liquid droplets, which are now widely appreciated in myriad cellular processes like RNA processing (Schmidt and Gorlich, 2016). Technological innovation in protein structural biology, biophysics, molecular dynamics simulations, and single-