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NMR structure of the
cyclin-dependent kinase inhibitor
Sic1 with the
ubiquitin ligase
Cdc4 (grey). Out of the nine
phosphorylation sites of Sic 1 (spheres) the contacts with T45 and S76 are shown (orange and blue).
The fuzzy linker region (shown by dotted line) of the
Ultrabithorax
transcription factor (orange) connects the
homedomain with the
Extradenticle
homedomain (blue) (PDB code 1bi).
Alternative splicing modulates the length of the fuzzy region and thus its DNA (grey)
binding affinity . Other regulatory fuzzy regions of Ultrabithorax are also shown by dotted lines.
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.
[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]
Regulatory pathways via fuzzy regions
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.
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