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Ubiquitin C-terminal hydrolase deubiquitinase BAP1 is an essential tumor suppressor involved in cell growth control, DNA damage response, and transcriptional regulation. As part of the Polycomb repression machinery, BAP1 is activated by the deubiquitinase adaptor domain of ASXL1 mediating gene repression by cleaving ubiquitin (Ub) from histone H2A in nucleosomes. The molecular mechanism of BAP1 activation by ASXL1 remains elusive, as no structures are available for either BAP1 or ASXL1. Here, we present the crystal structure of the BAP1 ortholog from Drosophila melanogaster, named Calypso, bound to its activator, ASX, homolog of ASXL1. Based on comparative structural and functional analysis, we propose a model for Ub binding by Calypso/ASX, uncover decisive structural elements responsible for ASX-mediated Calypso activation, and characterize the interaction with ubiquitinated nucleosomes. Our results give molecular insight into Calypso function and its regulation by ASX and provide the opportunity for the rational design of mechanism-based therapeutics to treat human BAP1/ASXL1-related tumors.
Pubmed ID: 30639226 RIS Download
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Portal for Macromolecular X-Ray Crystallography to produce and support an integrated suite of programs that allows researchers to determine macromolecular structures by X-ray crystallography, and other biophysical techniques. Used in the education and training of scientists in experimental structural biology for determination and analysis of protein structure.
View all literature mentionsA Python-based software suite for the automated determination of molecular structures using X-ray crystallography and other methods. Phenix includes programs for assessing data quality, experimental phasing, molecular replacement, model building, structure refinement, and validation. It also includes tools for reflection data and creating maps and models. Phenix can also be used for neutron crystallography. Tutorials and examples are available in the documentation tab.
View all literature mentionsSoftware for x-ray detection and processing single-crystal monochromatic diffraction data recorded by the rotation method. XDS can process data images from CCD-, imaging-plate-, multiwire-, and pixel-detectors in a variety of formats.
View all literature mentionsThis polyclonal targets Histone H2A (acidic patch)
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