Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor

Jung, S. K., Jeong, D. G., Chung, S. J., Kim, J. H., Park, B. C., Tonks, N. K., Ryu, S. E., Kim, S. J. (February 2010) Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor. FASEB J., 24 (2). pp. 560-569. ISSN 0892-6638

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URL: https://www.ncbi.nlm.nih.gov/pubmed/19858093
DOI: 10.1096/fj.09-143891

Abstract

Eya proteins are transcription factors that play pivotal roles in organ formation during development by mediating interactions between Sine Oculis (SO) and Dachshund (DAC). Remarkably, the transcriptional activity of Eya proteins is regulated by a dephosphorylating activity within its Eya domain (ED). However, the molecular basis for the link between catalytic and transcriptional activities remains unclear. Here we report the first description of the crystal structure of the ED of human Eya2 (ED-Eya2), determined at 2.4-angstrom resolution. In stark contrast to other members of the haloacid dehalogenase (HAD) family to which ED-Eya2 belongs, the helix-bundle motif (HBM) is elongated along the back of the catalytic site. This not only results in a structure that accommodates large protein substrates but also positions the catalytic and the SO-interacting sites on opposite faces, which suggests that SO binding is not directly affected by catalytic function. Based on the observation that the DAC-binding site is located between the catalytic core and SO binding sites within ED-Eya2, we propose that catalytic activity can be translated to SO binding through DAC, which acts as a transcriptional switch. We also captured at two stages of reaction cycles-acyl-phosphate intermediate and transition state of hydrolysis step, which provided a detailed view of reaction mechanism. The ED-Eya2 structure defined here serves as a model for other members of the Eya family and provides a framework for understanding the role of Eya phosphatase mutations in disease.-Jung, S.-K., Jeong, D. G., Chung, S. J., Kim, J. H., Park, B. C., Tonks, N. K., Ryu, S. E., Kim, S. J.. Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor. FASEB J. 24, 560-569 (2010). www.fasebj.org

Item Type: Paper
Uncontrolled Keywords: branchio-oto-renal syndrome eyes absent phosphatase halo-acid dehalogenase EYES-ABSENT GENE BRANCHIOOTORENAL SYNDROME PHOSPHOSERINE PHOSPHATASE DIFFRACTION DATA DROSOPHILA EYE HUMAN HOMOLOG MUTATIONS EYA1 COMPLEX BOR
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
organism description > animal > insect > Drosophila
Investigative techniques and equipment > X-Ray Diffraction
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: CSHL Librarian
Date: February 2010
Date Deposited: 30 Sep 2011 20:19
Last Modified: 21 Feb 2017 20:11
PMCID: PMC4048942
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15444

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