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Instruments / Technical Area	Publication Details	Published
Krios IV-Titan Krios IV at Diamond	Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex Mandy S. M. Wan , Reyhan Muhammad , Marios G. Koliopoulos , Theodoros I. Roumeliotis , Jyoti S. Choudhary , Claudio Alfieri Nature Communications 14 DOI: 10.1038/s41467-023-38276-0 Diamond Proposal Number(s): [21809] Open Access Show Abstract ▼ Abstract: Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.	May 2023
Krios II-Titan Krios II at Diamond	Structure of a nucleosome-bound MuvB transcription factor complex reveals DNA remodelling Marios G. Koliopoulos , Reyhan Muhammad , Theodoros I. Roumeliotis , Fabienne Beuron , Jyoti S. Choudhary , Claudio Alfieri Nature Communications 13 DOI: 10.1038/s41467-022-32798-9 Diamond Proposal Number(s): [21809] Open Access Show Abstract ▼ Abstract: Genes encoding the core cell cycle machinery are transcriptionally regulated by the MuvB family of protein complexes in a cell cycle-specific manner. Complexes of MuvB with the transcription factors B-MYB and FOXM1 activate mitotic genes during cell proliferation. The mechanisms of transcriptional regulation by these complexes are still poorly characterised. Here, we combine biochemical analysis and in vitro reconstitution, with structural analysis by cryo-electron microscopy and cross-linking mass spectrometry, to functionally examine these complexes. We find that the MuvB:B-MYB complex binds and remodels nucleosomes, thereby exposing nucleosomal DNA. This remodelling activity is supported by B-MYB which directly binds the remodelled DNA. Given the remodelling activity on the nucleosome, we propose that the MuvB:B-MYB complex functions as a pioneer transcription factor complex. In this work, we rationalise prior biochemical and cellular studies and provide a molecular framework of interactions on a protein complex that is key for cell cycle regulation.	Aug 2022
Krios I-Titan Krios I at Diamond	Molecular mechanisms of APC/C release from spindle assembly checkpoint inhibition by APC/C SUMOylation Stanislau Yatskevich , Jessie S. Kroonen , Claudio Alfieri , Thomas Tischer , Anna C. Howes , Linda Clijsters , Jing Yang , Ziguo Zhang , Kaige Yan , Alfred C. O. Vertegaal , David Barford Cell Reports 34 DOI: 10.1016/j.celrep.2021.108929 Diamond Proposal Number(s): [13708] Open Access Show Abstract ▼ Abstract: The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls cell cycle transitions. Its regulation by the spindle assembly checkpoint (SAC) is coordinated with the attachment of sister chromatids to the mitotic spindle. APC/C SUMOylation on APC4 ensures timely anaphase onset and chromosome segregation. To understand the structural and functional consequences of APC/C SUMOylation, we reconstituted SUMOylated APC/C for electron cryo-microscopy and biochemical analyses. SUMOylation of the APC/C causes a substantial rearrangement of the WHB domain of APC/C’s cullin subunit (APC2WHB). Although APC/CCdc20 SUMOylation results in a modest impact on normal APC/CCdc20 activity, repositioning APC2WHB reduces the affinity of APC/CCdc20 for the mitotic checkpoint complex (MCC), the effector of the SAC. This attenuates MCC-mediated suppression of APC/CCdc20 activity, allowing for more efficient ubiquitination of APC/CCdc20 substrates in the presence of the MCC. Thus, SUMOylation stimulates the reactivation of APC/CCdc20 when the SAC is silenced, contributing to timely anaphase onset.	Mar 2021

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