3hb1 | pdb_00003hb1
Crystal structure of ed-eya2 complexed with Alf3
Structural highlights
FunctionEYA2_HUMAN Tyrosine phosphatase that specifically dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph). 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Promotes efficient DNA repair by dephosphorylating H2AX, promoting the recruitment of DNA repair complexes containing MDC1. Its function as histone phosphatase probably explains its role in transcription regulation during organogenesis. Coactivates SIX1. Seems to coactivate SIX2, SIX4 and SIX5. Together with SIX1 and DACH2 seem to be involved in myogenesis. May be involved in development of the eye. Interaction with GNAZ and GNAI2 prevents nuclear translocation and transcriptional activity.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEya 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-A 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. Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor.,Jung SK, Jeong DG, Chung SJ, Kim JH, Park BC, Tonks NK, Ryu SE, Kim SJ FASEB J. 2010 Feb;24(2):560-9. Epub 2009 Oct 26. PMID:19858093[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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