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Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions

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The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome.

Section snippets

Structural heterogeneity of proteins and their complexes

Proteins are engaged in a complex array of physical and functional interactions with other proteins and macromolecules under physiological conditions. It is believed that the full molecular description of the resulting set of interactions (i.e. the interactome) will ultimately lead to a complete understanding of the functioning of the cell 1, 2. Current high-throughput studies on the expression, interactions and structure of all cellular constituents in the free and complexed states aim to

Static disorder in protein complexes

Structural heterogeneity can be a result of distinct, well-defined conformations. This might range from a few to a multitude of alternative structures that could be individually solved depending on the resolution of the technique applied. Distinct bound conformations might serve various functions by having different effects on the partner.

Dynamic disorder in complexes

Proteins, even in the bound state, can fluctuate between various structures of a dynamic ensemble. The disordered regions can carry important functions, such as increasing the conformational freedom and adaptability of two binding regions (clamp model), or providing a site for other binding partners or post-translational modifications (flanking model). At the extreme, disorder of the entire chain could provide an entirely novel solution to transient protein–protein interactions (random model).

Interactions without strict sequence constraints

The results of a range of unusual mutagenesis studies might also conform to the concept of fuzziness. In these special cases, no effect on the biological function is seen following the scrambling of the primary sequence of the IDP or IDR involved (Table 2). This suggests that a biological function that results from protein–protein interactions could be independent of the actual sequence. These observations are in sharp contrast to all existing models of protein–protein recognition, and even in

Concluding remarks: a structural and functional view of fuzziness

The observation of fuzziness in protein complexes raises two interdependent questions: (i) how can we interpret fuzziness structurally and (ii) what is the functional and evolutionary role of this phenomenon?

The structural view of fuzziness is straightforward in the case of the static models, when alternative bound conformations enabled by the adaptability of the isolated molecule emerge, in accord with the binding promiscuity already suggested for IDPs [51]. In dynamic cases, however, several

Acknowledgements

This research was supported by grants OTKA K60694 and F046164 from the Hungarian Scientific Research Fund, ETT 245/2006 from the Hungarian Ministry of Health, International Senior Research Fellowship ISRF 067595 from the Wellcome Trust (to P.T.), MRTN-CT-2005–019566 of the European FP6 and a Bolyai fellowship (to M.F.).

Glossary

CBD
β-catenin binding domain of Tcf4.
Cdc4p
cell-division cycle 4 protein, an E3 ubiquitin ligase that targets Sic1, a cyclin-dependent kinase (Cdk) inhibitor, for degradation.
CFTR
cystic fibrosis transmembrane conductance regulator, a phosphorylation-regulated Cl channel in the epithelial cell membrane.
CREB
cyclic AMP response element-binding protein, a transcription factor responding to elevated cAMP levels.
CTD
C-terminal domain of proteins.
DFF40
DNA fragmentation factor 40, responsible for

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