ORCID Profile
0000-0003-1121-8817
Current Organisation
Monash University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Epigenetics (incl. Genome Methylation and Epigenomics) | Biochemistry and Cell Biology | Structural Biology (incl. Macromolecular Modelling) |
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Technology
Publisher: Worldwide Protein Data Bank
Date: 16-01-2013
DOI: 10.2210/PDB4FWF/PDB
Publisher: Springer Science and Business Media LLC
Date: 26-01-2010
DOI: 10.1038/CR.2010.8
Abstract: Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain (PHD) finger protein 8 (PHF8) are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without alpha-ketoglutarate (alpha-KG) at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 (H3K9me2/1), but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.
Publisher: Worldwide Protein Data Bank
Date: 13-08-2014
DOI: 10.2210/PDB4QN1/PDB
Publisher: Worldwide Protein Data Bank
Date: 14-10-2015
DOI: 10.2210/PDB4Z31/PDB
Publisher: Worldwide Protein Data Bank
Date: 26-05-2021
DOI: 10.2210/PDB6V3Y/PDB
Publisher: Springer Science and Business Media LLC
Date: 22-10-2015
DOI: 10.1038/SREP15660
Abstract: Roquins are a family of highly conserved RNA-binding proteins that also contain a RING-type E3 ubiquitin ligase domain. They repress constitutive decay elements containing mRNAs and play a critical role in RNA homeostasis and immunological self-tolerance. Here we present the crystal structures of the RNA-binding region of Roquin paralog RC3H2 in both apo- and RNA-bound forms. The RNA-binding region has a bipartite architecture composed of ROQ and HEPN domains and can bind to stem-loop and double-stranded RNAs simultaneously. The two domains undergo a large orientation change to accommodate RNA duplex binding. We profiled E2 ubiquitin-conjugating enzymes that pair with Roquins and found that RC3H1 and RC3H2 interact with two sets of overlapping but not identical E2 enzymes to drive the assembly of polyubiquitin chains of different linkages. Crystal structures, small-angle X-ray scattering and E2 profiling revealed that while the two paralogs are highly homologous, RC3H2 and RC3H1 are different in their structures and functions. We also demonstrated that RNA duplex binding to RC3H2 cross-talks with its E3 ubiquitin ligase function using an in vitro auto-ubiquitination assay.
Publisher: Worldwide Protein Data Bank
Date: 13-03-2013
DOI: 10.2210/PDB4JDL/PDB
Publisher: Elsevier BV
Date: 08-2016
Publisher: Worldwide Protein Data Bank
Date: 14-10-2015
DOI: 10.2210/PDB4Z30/PDB
Publisher: Springer Science and Business Media LLC
Date: 25-12-2012
DOI: 10.1038/CR.2012.177
Publisher: Worldwide Protein Data Bank
Date: 24-06-2015
DOI: 10.2210/PDB4TVR/PDB
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.STR.2012.02.019
Abstract: Abscisic acid (ABA) controls many physiological processes and mediates adaptive responses to abiotic stresses. The ABA signaling mechanisms for abscisic acid receptors PYR/PYL/RCAR (PYLs) were reported. However, it remains unclear whether the molecular mechanisms are suitable for other PYLs. Here, complex structures of PYL3 with (+)-ABA, pyrabactin and HAB1 are reported. An unexpected trans-homodimer intermediate observed in the crystal is confirmed in solution. ABA-bound PYL3 greatly promotes the generation of monomeric PYL3, which can excessively increase the efficiency of inhibiting PP2Cs. Structure-guided biochemical experiments show that Ser195 accounts for the key intermediate. Interestingly, pyrabactin binds to PYL3 in a distinct nonproductive mode with gate closure, which sheds light on the design of agonists and antagonists for abscisic acid receptors. According to different conformations of ligand-bound PYLs, the PYLs family can be ided into three subclasses, among which the trans-dimeric subclass, represented by PYL3, reveals a distinct regulatory mechanism.
Publisher: Worldwide Protein Data Bank
Date: 26-05-2021
DOI: 10.2210/PDB6V3X/PDB
Publisher: Worldwide Protein Data Bank
Date: 22-04-2015
DOI: 10.2210/PDB4YWQ/PDB
Publisher: Worldwide Protein Data Bank
Date: 14-09-2011
DOI: 10.2210/PDB3OQU/PDB
Publisher: Springer Science and Business Media LLC
Date: 28-07-2021
DOI: 10.1038/S41467-021-24866-3
Abstract: The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identities. JARID2 is the only accessory subunit of PRC2 that known to trigger an allosteric activation of methyltransferase. Yet, this mechanism cannot be generalised to all PRC2 variants as, in vertebrates, JARID2 is mutually exclusive with most of the accessory subunits of PRC2. Here we provide functional and structural evidence that the vertebrate-specific PRC2 accessory subunit PALI1 emerged through a convergent evolution to mimic JARID2 at the molecular level. Mechanistically, PRC2 methylates PALI1 K1241, which then binds to the PRC2-regulatory subunit EED to allosterically activate PRC2. PALI1 K1241 is methylated in mouse and human cell lines and is essential for PALI1-induced allosteric activation of PRC2. High-resolution crystal structures revealed that PALI1 mimics the regulatory interactions formed between JARID2 and EED. Independently, PALI1 also facilitates DNA and nucleosome binding by PRC2. In acute myelogenous leukemia cells, overexpression of PALI1 leads to cell differentiation, with the phenotype altered by a separation-of-function PALI1 mutation, defective in allosteric activation and active in DNA binding. Collectively, we show that PALI1 facilitates catalysis and substrate binding by PRC2 and provide evidence that subunit-induced allosteric activation is a general property of holo-PRC2 complexes.
Publisher: Worldwide Protein Data Bank
Date: 16-01-2013
DOI: 10.2210/PDB4FWJ/PDB
Publisher: Worldwide Protein Data Bank
Date: 10-08-2011
DOI: 10.2210/PDB3OJI/PDB
Publisher: Elsevier BV
Date: 10-2021
Publisher: Worldwide Protein Data Bank
Date: 31-12-2014
DOI: 10.2210/PDB4X3G/PDB
Publisher: International Union of Crystallography (IUCr)
Date: 30-04-2013
Publisher: Springer Science and Business Media LLC
Date: 03-2019
Publisher: Elsevier BV
Date: 04-2014
Publisher: Worldwide Protein Data Bank
Date: 04-05-2016
DOI: 10.2210/PDB5JJW/PDB
Publisher: Worldwide Protein Data Bank
Date: 04-07-2018
DOI: 10.2210/PDB5WCH/PDB
Publisher: Worldwide Protein Data Bank
Date: 06-06-2012
DOI: 10.2210/PDB4DS8/PDB
Publisher: Cold Spring Harbor Laboratory
Date: 23-01-2023
DOI: 10.1101/2023.01.23.525163
Abstract: Microtubule regulation is highly controlled in nerve regeneration. Caltubin, a novel Lymnaea stagnalis protein, contains putative EF-hand calcium-binding motifs and promotes neuronal outgrowth in Lymnaea and mouse. Here, we generated cell-permeable caltubin proteins to investigate mechanisms underlying this effect. We observed increased neurite extension and outgrowth following injury in caltubin-treated mouse neurons compared to vehicle controls. Purified caltubin bound α-tubulin between its L391-V405 amino acids and promoted microtubule assembly. Caltubin competitively inhibited binding of tubulin tyrosine ligase, which catalyzes tubulin retyrosination, and increased the ratio of detyrosinated to tyrosinated tubulin. Our crystal structure analysis confirmed that caltubin has four Ca 2+ -binding EF-hand motifs, like calmodulin but has distinct peptide binding domains. Our work suggests a unique Ca 2+ -dependent regulatory mechanism of microtubule assembly by caltubin. This may represent an essential mechanism of axonal regulation, which may optimize its activity in response to various calcium states, both physiological and following injury.
Publisher: Worldwide Protein Data Bank
Date: 16-01-2013
DOI: 10.2210/PDB4FWE/PDB
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.BBAGEN.2016.10.019
Abstract: Seven in absentia homologs (SIAHs) comprise a family of highly conserved E3 ubiquitin ligases that play an important role in regulating signalling pathways in tumorigenesis, including the DNA damage repair and hypoxia response pathways. SIAH1 and SIAH2 have been found to function as a tumour repressor and a proto-oncogene, respectively, despite the high sequence identity of their substrate binding domains (SBDs). Ubiquitin-specific protease USP19 is a deubiquitinase that forms a complex with SIAHs and counteracts the ligase function. Much effort has been made to find selective inhibitors of the SIAHs E3 ligases. Menadione was reported to inhibit SIAH2 specifically. We used X-ray crystallography, peptide array, bioinformatic analysis, and biophysical techniques to characterize the structure and interaction of SIAHs with deubiquitinases and literature reported compounds. We solved the crystal structures of SIAH1 in complex with a USP19 peptide and of the apo form SIAH2. Phylogenetic analysis revealed the SIAH/USP19 complex is conserved in evolution. We demonstrated that menadione destabilizes both SIAH1 and SIAH2 non-specifically through covalent modification. The SBDs of SIAH E3 ligases are structurally similar with a subtle stability difference. USP19 is the only deubiquitinase that directly binds to SIAHs through the substrate binding pocket. Menadione is not a specific inhibitor for SIAH2. The crystallographic models provide structural insights into the substrate binding of the SIAH family E3 ubiquitin ligases that are critically involved in regulating cancer-related pathways. Our results suggest caution should be taken when using menadione as a specific SIAH2 inhibitor.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Portland Press Ltd.
Date: 26-03-2021
DOI: 10.1042/BST20200238
Abstract: Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as ex les. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.
Publisher: Worldwide Protein Data Bank
Date: 04-05-2016
DOI: 10.2210/PDB5JJX/PDB
Publisher: Public Library of Science (PLoS)
Date: 02-07-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 26-03-2019
Abstract: USP9X is a conserved deubiquitinase (DUB) that regulates multiple cellular processes. Dysregulation of USP9X has been linked to cancers and X-linked intellectual disability. Here, we report the crystal structure of the USP9X catalytic domain at 2.5-Å resolution. The structure reveals a canonical USP-fold comprised of fingers, palm, and thumb subdomains, as well as an unusual β-hairpin insertion. The catalytic triad of USP9X is aligned in an active configuration. USP9X is exclusively active against ubiquitin (Ub) but not Ub-like modifiers. Cleavage assays with di-, tri-, and tetraUb chains show that the USP9X catalytic domain has a clear preference for K11-, followed by K63-, K48-, and K6-linked polyUb chains. Using a set of activity-based diUb and triUb probes (ABPs), we demonstrate that the USP9X catalytic domain has an exo-cleavage preference for K48- and endo-cleavage preference for K11-linked polyUb chains. The structure model and biochemical data suggest that the USP9X catalytic domain harbors three Ub binding sites, and a zinc finger in the fingers subdomain and the β-hairpin insertion both play important roles in polyUb chain processing and linkage specificity. Furthermore, unexpected labeling of a secondary, noncatalytic cysteine located on a blocking loop adjacent to the catalytic site by K11-diUb ABP implicates a previously unreported mechanism of polyUb chain recognition. The structural features of USP9X revealed in our study are critical for understanding its DUB activity. The new Ub-based ABPs form a set of valuable tools to understand polyUb chain processing by the cysteine protease class of DUBs.
Publisher: Worldwide Protein Data Bank
Date: 23-11-2016
DOI: 10.2210/PDB5TF2/PDB
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2015
Abstract: The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2–RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2–RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11–MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.
Publisher: Worldwide Protein Data Bank
Date: 06-06-2012
DOI: 10.2210/PDB4DSB/PDB
Publisher: Worldwide Protein Data Bank
Date: 17-02-2016
DOI: 10.2210/PDB5H9M/PDB
Start Date: 2021
End Date: 2026
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 12-2020
Amount: $343,551.00
Funder: Australian Research Council
View Funded Activity