Target-binding behavior of IDPs via pre-structured motifs

Abstract

Pre-Structured Motifs (PreSMos) are transient secondary structures observed in many intrinsically disordered proteins (IDPs) and serve as protein target-binding hot spots. The prefix "pre" highlights that PreSMos exist a priori in the target-unbound state of IDPs as the active pockets of globular proteins pre-exist before target binding. Therefore, a PreSMo is an "active site" of an IDP; it is not a spatial pocket, but rather a secondary structural motif. The classical and perhaps the most effective approach to understand the function of a protein has been to determine and investigate its structure. Ironically or by definition IDPs do not possess structure (here structure refers to tertiary structure only). Are IDPs then entirely structureless? The PreSMos provide us with an atomic-resolution answer to this question. For target binding, IDPs do not rely on the spatial pockets afforded by tertiary or higher structures. Instead, they utilize the PreSMos possessing particular conformations that highly presage the target-bound conformations. PreSMos are recognized or captured by targets via conformational selection (CS) before their conformations eventually become stabilized via structural induction into more ordered bound structures. Using PreSMos, a number of, if not all, IDPs can bind targets following a sequential pathway of CS followed by an induced fit (IF). This chapter presents several important PreSMos implicated in cancers, neurodegenerative diseases, and other diseases along with discussions on their conformational details that mediate target binding, a structural rationale for unstructured proteins.