Multiple Intrinsically Disordered Sequences Alter DNA Binding by the Homeodomain of the Drosophila Hox Protein Ultrabithorax

Liu, Ying; Matthews, Kathleen S.; Bondos, Sarah E.

doi:10.1074/jbc.m800375200

Cited by 82 publications

(157 citation statements)

References 100 publications

(170 reference statements)

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“…The evolution of a specific PPI between HoxA11 and Foxo1a is potentially another example of intramolecular regulation of transcription factor protein activities. For instance, both the DNA-binding affinity and specificity of the Ubx protein are influenced by intramolecular interactions between the homeodomain and the rest of the molecule (34,35). It is interesting that these "regulatory" interactions are linked to intrinsically unstructured parts of the protein (34,36,37) in many cases, because the amino-terminal region of HoxA11 is predicted to contain two unstructured regions (38) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation

Brayer

Lynch

Wagner

2011

Proc. Natl. Acad. Sci. U.S.A.

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Current models of developmental evolution suggest changes in gene regulation underlie the evolution of morphology. Despite the fact that protein complexes regulate gene expression, the evolution of regulatory protein complexes is rarely studied. Here, we investigate the evolution of a protein-protein interaction (PPI) between Homeobox A11 (HoxA11) and Forkhead box 01A (Foxo1a). Using extant and "resurrected" ancestral proteins, we show that the physical interaction between HoxA11 and Foxo1a originated in the mammalian stem lineage. Functional divergence tests and coimmunoprecipitation with heterologous protein pairs indicate that the evolution of interaction was attributable to changes in HoxA11, and deletion studies demonstrate that the interaction interface is located in the homeodomain region of HoxA11. However, there are no changes in amino acid sequence in the homeodomain region during this time period, indicating that the origin of the derived PPI was attributable to changes outside the binding interface. We infer that the amino acid substitutions in HoxA11 altered Foxo1a's access to the conserved binding interface at the HoxA11 homeodomain. We also found an expansion in the number of paired Hox/Fox binding sites in the genomes of mammalian lineage species suggesting the complex has a biological function. Our data indicate that the physical interaction between HoxA11 and Foxo1a evolved through noninterface changes that facilitate the PPI, which prevents inappropriate interactions, rather than through the evolution of a novel binding interface. We speculate that evolutionary changes of intramolecular regulation have limited pleiotropic effects compared with changes to interaction domains themselves.protein-protein interaction evolution | transcription factor evolution C hanges in gene regulation are the driving force in the origin and evolution of novel phenotypes. Gene expression is coordinated by the formation of multiprotein complexes that bind to cis-regulatory promoter and enhancer regions for target genes and activate or repress transcription in a signal-dependent fashion (1-3). There is strong evidence that changes in both cisregulatory elements and regulatory proteins, such as transcription factors, have led to gene regulatory evolution (4-12). However, the mechanisms by which transcription factor evolution affects gene regulation are poorly understood. For example, it has been suggested that the evolution of novel protein-protein interactions (PPIs), posttranslational modifications, and DNA-and ligandbinding specificities may all contribute to the origin of regulatory activities in transcription factors; however, to date, few studies have carefully dissected potential mechanisms.Here, we address this question by investigating the evolution of the physical interaction between two transcription factors, Homeobox A11 (HoxA11) and Forkhead box 01A (Foxo1a), which play a major role in regulating gene expression in endometrial stromal cells during pregnancy in placental mammals (8,13). By examining the a...

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Section: Discussionmentioning

confidence: 99%

Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation

Brayer

Lynch

Wagner

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…intrasteric regulation, 104 autoinhibition, 105,106 intramolecular regulation, 107 active-site directed regulation, 108 signaling conduit function, 109 motif exposure, 110 or neither of these terms [111][112][113] (cf. Table 2).…”

Section: Novel Type Of Allostery In Multidomain Proteinsmentioning

confidence: 99%

Multisteric Regulation by Structural Disorder in Modular Signaling Proteins: An Extension of the Concept of Allostery

2013

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“…In the third example, disorder predictions helped to define studies showing that alternative splicing of a disordered region of a hox protein plays a key role in the development of bilateral symmetry in organisms ranging from drosophila to humans [69]. Work in progress shows that the DNA-binding affinities to a number of different DNA targets become altered as a result of the alternative splicing in the disordered region.…”

Section: Introductionmentioning

confidence: 99%

Predicting intrinsic disorder in proteins: an overview

et al. 2009

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The discovery of intrinsically disordered proteins (IDP) (i.e., biologically active proteins that do not possess stable secondary and/or tertiary structures) came as an unexpected surprise, as the existence of such proteins is in contradiction to the traditional "sequence→structure→function" paradigm. Accurate prediction of a protein's predisposition to be intrinsically disordered is a necessary prerequisite for the further understanding of principles and mechanisms of protein folding and function, and is a key for the elaboration of a new structural and functional hierarchy of proteins. Therefore, prediction of IDPs has attracted the attention of many researchers, and a number of prediction tools have been developed. Predictions of disorder, in turn, are playing major roles in directing laboratory experiments that are leading to the discovery of ever more disordered proteins, and thereby leading to a positive feedback loop in the investigation of these proteins. In this review of algorithms for intrinsic disorder prediction, the basic concepts of various prediction methods for IDPs are summarized, the strengths and shortcomings of many of the methods are analyzed, and the difficulties and directions of future development of IDP prediction techniques are discussed.

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Multiple Intrinsically Disordered Sequences Alter DNA Binding by the Homeodomain of the Drosophila Hox Protein Ultrabithorax

Cited by 82 publications

References 100 publications

Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation

Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation

Multisteric Regulation by Structural Disorder in Modular Signaling Proteins: An Extension of the Concept of Allostery

Predicting intrinsic disorder in proteins: an overview

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