Fuzzy complexes: Specific binding without complete folding

Abstract

a b s t r a c tSpecific molecular recognition is assumed to require a well-defined set of contacts and devoid of conformational and interaction ambiguities. Growing experimental evidence demonstrates however, that structural multiplicity or dynamic disorder can be retained in protein complexes, termed as fuzziness. Fuzzy regions establish alternative contacts between specific partners usually via transient interactions. Nature often tailors the dynamic properties of these segments via post-translational modifications or alternative splicing to fine-tune affinity. Most experimentally characterized fuzzy complexes are involved in regulation of gene-expression, signal transduction and cell-cycle regulation. Fuzziness is also characteristic to viral protein complexes, cytoskeleton structure, and surprisingly in a few metabolic enzymes. A plausible role of fuzzy complexes in increasing half-life of intrinsically disordered proteins is also discussed.

The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules

“…In the case of dynamic disorder, the IDRs retain conformational freedom within the assembly and will be referred to as fuzzy regions or dynamic IDRs, to distinguish them from IDRs that fold upon binding. These dynamic IDRs within higher-order structures may link separate binding modules to increase their local concentration, exert transient interactions to influence adjacent binding elements, facilitate allostery, or promote intramolecular autoinhibition (Fuxreiter, 2012; Sharma et al, 2015) via well-characterized mechanisms (see examples in FuzDB, http://protdyn-database.org). …”

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins

“…Although an interaction of an IDP/IDPR with its binding partner is often accompanied by a disorder-to-order transition resulting in a (partial) folding of an IDP (9, 38, 50, 53, 54, 56 -59), many IDPs/IDPRs form fuzzy complexes in which they remain predominantly disordered, at least outside the binding interface (61)(62)(63)(64)(65)(66)(67)(68). Similar to the disordered regions of unbound IDPs, these under-folded, fuzzy regions of bound IDPs/IDPRs have multiple functions, e.g.…”

“…Similar to the disordered regions of unbound IDPs, these under-folded, fuzzy regions of bound IDPs/IDPRs have multiple functions, e.g. serving as alternative contacts for specific partners, usually via transient interactions and finetuned by PTMs (68).…”

Mechanisms of DNA-binding specificity and functional gene regulation by transcription factors

“…This type of transient interaction is termed a fuzzy complex, as reviewed in Ref. [61] and highlights roles for intrinsically disordered regions in regulation outside the mechanism of folding on binding.…”