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Connecting protein structure with predictions of regulatory sites.

ABSTRACT: A common task posed by microarray experiments is to infer the binding site preferences for a known transcription factor from a collection of genes that it regulates and to ascertain whether the factor acts alone or in a complex. The converse problem can also be posed: Given a collection of binding sites, can the regulatory factor or complex of factors be inferred? Both tasks are substantially facilitated by using relatively simple homology models for protein-DNA interactions, as well as the rapidly expanding protein structure database. For budding yeast, we are able to construct reliable structural models for 67 transcription factors and with them redetermine factor binding sites by using a Bayesian Gibbs sampling algorithm and an extensive protein localization data set. For 49 factors in common with a prior analysis of this data set (based largely on phylogenetic conservation), we find that half of the previously predicted binding motifs are in need of some revision. We also solve the inverse problem of ascertaining the factors from the binding sites by assigning a correct protein fold to 25 of the 49 cases from a previous study. Our approach is easily extended to other organisms, including higher eukaryotes. Our study highlights the utility of enlarging current structural genomics projects that exhaustively sample fold structure space to include all factors with significantly different DNA-binding specificities.

SUBMITTER: Morozov AV

PROVIDER: S-EPMC1855371 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Connecting protein structure with predictions of regulatory sites.

Morozov Alexandre V AV Siggia Eric D ED

Proceedings of the National Academy of Sciences of the United States of America 20070416 17

A common task posed by microarray experiments is to infer the binding site preferences for a known transcription factor from a collection of genes that it regulates and to ascertain whether the factor acts alone or in a complex. The converse problem can also be posed: Given a collection of binding sites, can the regulatory factor or complex of factors be inferred? Both tasks are substantially facilitated by using relatively simple homology models for protein-DNA interactions, as well as the rapi ...[more]

PMID: 17438293

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Project description:Although most proteins conform to the classical one-structure/one-function paradigm, an increasing number of proteins with dual structures and functions have been discovered. In response to cellular stimuli, such proteins undergo structural changes sufficiently dramatic to remodel even their secondary structures and domain organization. This "fold-switching" capability fosters protein multi-functionality, enabling cells to establish tight control over various biochemical processes. Accurate predictions of fold-switching proteins could both suggest underlying mechanisms for uncharacterized biological processes and reveal potential drug targets. Recently, we developed a prediction method for fold-switching proteins using structure-based thermodynamic calculations and discrepancies between predicted and experimentally determined protein secondary structure (Porter and Looger, Proc Natl Acad Sci U S A 2018; 115:5968-5973). Here we seek to leverage the negative information found in these secondary structure prediction discrepancies. To do this, we quantified secondary structure prediction accuracies of 192 known fold-switching regions (FSRs) within solved protein structures found in the Protein Data Bank (PDB). We find that the secondary structure prediction accuracies for these FSRs vary widely. Inaccurate secondary structure predictions are strongly associated with fold-switching proteins compared to equally long segments of non-fold-switching proteins selected at random. These inaccurate predictions are enriched in helix-to-strand and strand-to-coil discrepancies. Finally, we find that most proteins with inaccurate secondary structure predictions are underrepresented in the PDB compared with their alternatively folded cognates, suggesting that unequal representation of fold-switching conformers within the PDB could be an important cause of inaccurate secondary structure predictions. These results demonstrate that inconsistent secondary structure predictions can serve as a useful preliminary marker of fold switching.

Dataset Information

Connecting protein structure with predictions of regulatory sites.

Publications

Connecting protein structure with predictions of regulatory sites.

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