6hgc
Structure of Calypso in complex with DEUBAD of ASX
Structural highlights
Function[CALYP_DROME] Polycomb group (PcG) protein. Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-118' (H2AK118ub1). Does not deubiquitinate monoubiquitinated histone H2B. Required to maintain the transcriptionally repressive state of homeotic genes throughout development. The PR-DUB complex has weak or no activity toward 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.[1] [ASX_DROME] Atypical Polycomb group protein, which may be involved in both Polycomb group (PcG) and trithorax group (trxG) complexes. Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-118' (H2AK118ub1). Does not deubiquitinate monoubiquitinated histone H2B. Required to maintain the transcriptionally repressive state of homeotic genes throughout development. The PR-DUB complex has weak or no activity toward 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. PcG and trxG proteins act by forming multiprotein complexes, which are respectively required to maintain the transcriptionally repressive and transcriptionally active state of homeotic genes throughout development. PcG and trxG protein complexes are not required to initiate repression and activation, but to maintain it during later stages of development.[2] [3] Publication Abstract from PubMedUbiquitin 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. Structural Basis for the Activation of the Deubiquitinase Calypso by the Polycomb Protein ASX.,De I, Chittock EC, Grotsch H, Miller TCR, McCarthy AA, Muller CW Structure. 2019 Mar 5;27(3):528-536.e4. doi: 10.1016/j.str.2018.11.013. Epub 2019, Jan 10. PMID:30639226[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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