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Prediction of the rotational tumbling time for proteins with disordered segments.

ABSTRACT: For well-structured, rigid proteins, the prediction of rotational tumbling time (tau(c)) using atomic coordinates is reasonably accurate, but is inaccurate for proteins with long unstructured sequences. Under physiological conditions, many proteins contain long disordered segments that play important regulatory roles in fundamental biological events including signal transduction and molecular recognition. Here we describe an ensemble approach to the boundary element method that accurately predicts tau(c) for such proteins by introducing two layers of molecular surfaces whose correlated velocities decay exponentially with distance. Reliable prediction of tau(c) will help to detect intra- and intermolecular interactions and conformational switches between more ordered and less ordered states of the disordered segments. The method has been extensively validated using 12 reference proteins with 14 to 103 disordered residues at the N- and/or C-terminus and has been successfully employed to explain a set of published results on a system that incorporates a conformational switch.

SUBMITTER: Bae SH

PROVIDER: S-EPMC2694746 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Prediction of the rotational tumbling time for proteins with disordered segments.

Bae Sung-Hun SH Dyson H Jane HJ Wright Peter E PE

Journal of the American Chemical Society 20090501 19

For well-structured, rigid proteins, the prediction of rotational tumbling time (tau(c)) using atomic coordinates is reasonably accurate, but is inaccurate for proteins with long unstructured sequences. Under physiological conditions, many proteins contain long disordered segments that play important regulatory roles in fundamental biological events including signal transduction and molecular recognition. Here we describe an ensemble approach to the boundary element method that accurately predic ...[more]

PMID: 19391622

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Project description:Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins.

Project description:BACKGROUND:Although structural domains in proteins (SDs) are important, half of the regions in the human proteome are currently left with no SD assignments. These unassigned regions consist not only of novel SDs, but also of intrinsically disordered (ID) regions since proteins, especially those in eukaryotes, generally contain a significant fraction of ID regions. As ID regions can be inferred from amino acid sequences, a method that combines SD and ID region assignments can determine the fractions of SDs and ID regions in any proteome. RESULTS:In contrast to other available ID prediction programs that merely identify likely ID regions, the DICHOT system we previously developed classifies the entire protein sequence into SDs and ID regions. Application of DICHOT to the human proteome revealed that residue-wise ID regions constitute 35%, SDs with similarity to PDB structures comprise 52%, while SDs with no similarity to PDB structures account for the remaining 13%. The last group consists of novel structural domains, termed cryptic domains, which serve as good targets of structural genomics. The DICHOT method applied to the proteomes of other model organisms indicated that eukaryotes generally have high ID contents, while prokaryotes do not. In human proteins, ID contents differ among subcellular localizations: nuclear proteins had the highest residue-wise ID fraction (47%), while mitochondrial proteins exhibited the lowest (13%). Phosphorylation and O-linked glycosylation sites were found to be located preferentially in ID regions. As O-linked glycans are attached to residues in the extracellular regions of proteins, the modification is likely to protect the ID regions from proteolytic cleavage in the extracellular environment. Alternative splicing events tend to occur more frequently in ID regions. We interpret this as evidence that natural selection is operating at the protein level in alternative splicing. CONCLUSIONS:We classified entire regions of proteins into the two categories, SDs and ID regions and thereby obtained various kinds of complete genome-wide statistics. The results of the present study are important basic information for understanding protein structural architectures and have been made publicly available at http://spock.genes.nig.ac.jp/~genome/DICHOT.

Dataset Information

Prediction of the rotational tumbling time for proteins with disordered segments.

Publications

Prediction of the rotational tumbling time for proteins with disordered segments.

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