Fuzzy complex

Fuzzy complexes are protein complexes, where structural ambiguity or multiplicity exists and is required for biological function.^[1][2] Alteration, truncation or removal of conformationally ambiguous regions impacts the activity of the corresponding complex.^[3][4][5] Fuzzy complexes are generally formed by intrinsically disordered proteins.^[6][7] Structural multiplicity usually underlies functional multiplicity of protein complexes ^[8][9][10] following a fuzzy logic. Distinct binding modes of the nucleosome are also regarded as a special case of fuzziness.^[11][12]

For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations.^[13] This phenomenon is defined fuzziness. The most pertinent example is the cyclin-dependent kinase inhibitor Sic1, which binds to the SCF subunit of Cdc4 in a phosphorylation dependent manner.^[14] No regular secondary structures are gained upon phosphorylation and the different phosphorylation sites interchange in the complex.^[15]

Structural ambiguity in protein complexes covers a wide spectrum.^[1] In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.^[16] Clamp,^[17] flanking ^[18][19] and random complexes^[20][21] are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs.^[22] Flanking regions are tolerant to sequence changes as long as the amino acid composition is maintained, for example in case of linker histone C-terminal domains ^[23] and H4 histone N-terminal domains.^[24]

Fuzzy regions modulate the conformational equilibrium ^[25] or flexibility ^[3][26] of the binding interface via transient interactions.^[27] Dynamic regions can also compete with binding sites^[28] or tether them to the target.^[29] Modifications of fuzzy regions by further interactions,^[8][30] or posttranslational modifications^[31][32] impact binding affinity or specificity. Alternative splicing can modulate the length of fuzzy regions resulting in context-dependent binding (e.g. tissue-specificity) on the complex.^[33][34][35] EGF/MAPK, TGF-β and WNT/Wingless signaling pathways employ tissue-specific fuzzy regions.