The eukaryotic cell is a bustling collection of macromolecules acting cooperatively to mediate the functions required for cell viability. Specific, context-dependent and tightly controlled physical interactions between these cellular components govern the necessary physiological processes, from cell division to cell death. The specificity, conditionality, and regulation of these binding events depend on communication between the interacting molecules and their surroundings. For proteins, most of this communication is mediated by a variety of modules that are embedded within the protein sequence, can bind a wide array of ligands, and have catalytic, regulatory, or scaffolding activity. These functional units enable proteins to sense, integrate, and transmit environmental and cell state indicators and concomitantly instigate cellular decisions based on the information available to the system. The diversity of the cellular functions assigned to proteins is matched by the remarkable variety of their interaction modules, each with recognizably distinct binding properties. Globular domains mediating high-affinity interactions, such as those stabilizing multisubunit molecular machines, 1, 2 are classically seen as the archetypal protein interaction module, a perception that stems from the obsolete assertion that a protein requires a well-defined, properly folded three-dimensional structure in order to perform its biological function. 3 Currently, the wellstructured globular domains provide the majority of characterized protein interaction interfaces. However, the past decade has revealed that unstructured regions of the proteome play a central role in many dynamic cellular processes and that binding sites lacking a stable predefined conformation mediate a significant fraction (perhaps even the majority) of regulatory protein interactions within the cell. 3− 14 This has led to the development of an exciting new field in molecular biology that is progressively unraveling the role of these intrinsically disordered regions (IDRs), as evidenced by the increasing discovery rate of novel modules within these regions and the functions thereof. 14, 15 However, despite recent advances and an increasing recognition of their importance, the mechanisms by which IDRs direct and regulate protein and pathway function are not well understood.

The most common functional modules within IDRs are composed of short stretches of adjacent amino acids. These compact, linear protein interaction sites are known as short linear motifs (SLiMs), also being referred to as linear motifs (LMs), molecular recognition features (MoRFs), or mini-Motifs. 15− 18 Depending on the partner proteins that recognize them, these sites can facilitate a diverse set of functions including targeting a protein to a specific subcellular location, determining the modification state of a protein, controlling the stability of a protein, and regulating the context-dependent activity of a protein. 15, 19 Hence, SLiMs are imperative for dynamic and robust control of cell physiology. The current census of SLiMs is split unequally between ligand motifs that mediate protein− protein interactions (see section 4. 1) and post-translational modification motifs, which are directly recognized and targeted for post-translational modification (PTM) by regulatory enzymes (see section 4.2). The Eukaryotic Linear Motif (ELM) resource (http://elm. eu. org) is the most comprehensive repository of experimentally validated SLiMs, containing∼ 2000 ligand motif instances recognized by∼ 100 nonenzymatic globular domain families. 15 In contrast, around 100 000 sites recognized and modified by enzymatic globular domains (many of which recognize a modification motif�…