Trends in Biochemical Sciences
OpinionFuzzy complexes: polymorphism and structural disorder in protein–protein interactions
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
References (58)
- et al.
Ten thousand interactions for the molecular biologist
Nat. Biotechnol.
(2004) - et al.
Structural systems biology: modelling protein interactions
Nat. Rev. Mol. Cell Biol.
(2006) Intrinsically unstructured proteins
Trends Biochem. Sci.
(2002)The interplay between structure and function in intrinsically unstructured proteins
FEBS Lett.
(2005)Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling
J. Mol. Recognit.
(2005)- et al.
Intrinsically unstructured proteins and their functions
Nat. Rev. Mol. Cell Biol.
(2005) Intrinsic protein disorder in complete genomes
Genome Inform. Ser. Workshop Genome Inform.
(2000)Prediction and functional analysis of native disorder in proteins from the three kingdoms of life
J. Mol. Biol.
(2004)Prevalent structural disorder in E. coli and S. cerevisiae proteomes
J. Proteome Res.
(2006)- et al.
Coupling of folding and binding for unstructured proteins
Curr. Opin. Struct. Biol.
(2002)