6HGC

Structure of Calypso in complex with DEUBAD of ASX

Summary for 6HGC

• Entry DOI: 10.2210/pdb6hgc/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase calypso,Ubiquitin carboxyl-terminal hydrolase calypso, Polycomb protein Asx (3 entities in total)
• Functional Keywords: deubiquitinase, polycomb group proteins, transcription, gene repression, hydrolase
• Biological source: Drosophila melanogaster (Fruit fly); More
• Total number of polymer chains: 3
• Total formula weight: 85808.25

Authors

De, I.,Chittock, E.C.,Groetsch, H.,Miller, T.C.R.,McCarthy, A.A.,Mueller, C.W. (deposition date: 2018-08-23, release date: 2019-01-23, Last modification date: 2024-05-15)

Primary citation

De, I.,Chittock, E.C.,Grotsch, H.,Miller, T.C.R.,McCarthy, A.A.,Muller, C.W.
Structural Basis for the Activation of the Deubiquitinase Calypso by the Polycomb Protein ASX.
Structure, 27:528-536.e4, 2019

PubMed Abstract: 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: 30639226
DOI: 10.1016/j.str.2018.11.013

Experimental method

X-RAY DIFFRACTION (3.02 Å)