Fuzzy complex explained

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]

Historical background

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]

Classification of fuzzy complexes

Structural ambiguity in protein complexes covers a wide spectrum. 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]

Regulatory pathways via fuzzy regions

Fuzzy regions modulate the conformational equilibrium [25] or flexibility [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,[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.

Notes and References

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  2. Fuxreiter, M. & Tompa, P. (2011) Fuzziness: Structural Disorder in Protein Complexes Austin, New York.
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