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Intrinsic disorder in protein interactions: insights from a comprehensive structural analysis.

ABSTRACT: We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon complex formation and can be localized to binding interfaces. Moreover, analysis of disorder in protein complexes depicts a significant fraction of intrinsically disordered regions, with up to one third of all residues being disordered. We find that the disorder in homodimers, especially in symmetrical homodimers, is significantly higher than in heterodimers and offer an explanation for this interesting phenomenon. We argue that the mechanisms of regulation of binding specificity through disordered regions in complexes can be as common as for unbound monomeric proteins. The fascinating diversity of roles of disordered regions in various biological processes and protein oligomeric forms shown in our study may be a subject of future endeavors in this area.

SUBMITTER: Fong JH

PROVIDER: S-EPMC2646137 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Intrinsic disorder in protein interactions: insights from a comprehensive structural analysis.

Fong Jessica H JH Shoemaker Benjamin A BA Garbuzynskiy Sergiy O SO Lobanov Michail Y MY Galzitskaya Oxana V OV Panchenko Anna R AR

PLoS computational biology 20090313 3

We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon complex formation and can be localized to binding interfaces. Moreover, analysis of disorder in protein complexes depicts a significant fraction of intrinsically disordered regions, wi ...[more]

PMID: 19282967

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Project description:The importance of unstructured biology has quickly grown during the last decades accompanying the explosion of the number of experimentally resolved protein structures. The idea that structural disorder might be a novel mechanism of protein interaction is widespread in the literature, although the number of statistically significant structural studies supporting this idea is surprisingly low. At variance with previous works, our conclusions rely exclusively on a large-scale analysis of all the 134337 X-ray crystallographic structures of the Protein Data Bank averaged over clusters of almost identical protein sequences. In this work, we explore the complexity of the organisation of all the interaction interfaces observed when a protein lies in alternative complexes, showing that interfaces progressively add up in a hierarchical way, which is reflected in a logarithmic law for the size of the union of the interface regions on the number of distinct interfaces. We further investigate the connection of this complexity with different measures of structural disorder: the standard missing residues and a new definition, called "soft disorder", that covers all the flexible and structurally amorphous residues of a protein. We show evidences that both the interaction interfaces and the soft disordered regions tend to involve roughly the same amino-acids of the protein, and preliminary results suggesting that soft disorder spots those surface regions where new interfaces are progressively accommodated by complex formation. In fact, our results suggest that structurally disordered regions not only carry crucial information about the location of alternative interfaces within complexes, but also about the order of the assembly. We verify these hypotheses in several examples, such as the DNA binding domains of P53 and P73, the C3 exoenzyme, and two known biological orders of assembly. We finally compare our measures of structural disorder with several disorder bioinformatics predictors, showing that these latter are optimised to predict the residues that are missing in all the alternative structures of a protein and they are not able to catch the progressive evolution of the disordered regions upon complex formation. Yet, the predicted residues, when not missing, tend to be characterised as soft disordered regions.

Dataset Information

Intrinsic disorder in protein interactions: insights from a comprehensive structural analysis.

Publications

Intrinsic disorder in protein interactions: insights from a comprehensive structural analysis.

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