A5051173642- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- 14-3-3 protein interactions
- Microtubule and mitosis dynamics
- Protein Kinase Regulation and GTPase Signaling
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- ATP Synthase and ATPases Research
- Bone Metabolism and Diseases
- Axon Guidance and Neuronal Signaling
- Hippo pathway signaling and YAP/TAZ
- Natural Antidiabetic Agents Studies
- Cell death mechanisms and regulation
- Ion Transport and Channel Regulation
- Autophagy in Disease and Therapy
- Ferroptosis and cancer prognosis
- Genetics and Neurodevelopmental Disorders
- Diabetes Treatment and Management
- Cancer, Lipids, and Metabolism
- Liver physiology and pathology
- Protein Tyrosine Phosphatases
- DNA Repair Mechanisms
- Lipid metabolism and disorders
- Magnetic and Electromagnetic Effects
- Calcium signaling and nucleotide metabolism
The University of Melbourne
2015-2025
St Vincents Institute of Medical Research
2014-2025
Walter and Eliza Hall Institute of Medical Research
2021-2025
University of Dundee
2024
MRC Protein Phosphorylation and Ubiquitylation Unit
2024
St Vincent's Hospital
2018-2019
The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis, making it therapeutic target diseases such as type 2 diabetes and obesity. AMPK signaling triggered by phosphorylation on the α subunit activation loop Thr172 upstream kinases. Dephosphorylated, naive thought to be catalytically inactive insensitive allosteric regulation AMP direct AMPK-activating drugs A-769662. Here we show that A-769662 activates independently of...
Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results poor prognoses, as established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a selectivity profile. Here we identify pyrimidine derivative SBI-0206965 direct inhibitor. inhibits with 40-fold greater potency markedly lower promiscuity than C...
AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 critically dependent on phosphorylation Ser108 in β1 regulatory subunit. Here, we show possible role cell cycle regulation promotion pro-survival pathways response to stress. We identify autophagy initiator Unc-51-like 1 (ULK1) as β1-Ser108 cells. Cellular ULK1 was β-subunit myristoylation, stress...
Abstract Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until remodeled. The interconnected osteocyte network within the matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. not caused by low...
Abstract Caspase-2, one of the most evolutionarily conserved members caspase family, is an important regulator cellular response to oxidative stress. Given that ferroptosis suppressed by antioxidant defense pathways, such as involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized caspase-2 may play a role in regulating ferroptosis. This study provides first demonstration and unprecedented function protecting cancer cells from undergoing ferroptotic cell death. Specifically,...
Plasmodium falciparum Pfs230 and Pfs48/45, part of a core fertilization complex, are leading malaria transmission-blocking vaccine candidates. However, how the two proteins interact is unknown. Here we report 3.36 Å resolution cryo-electron microscopy structure endogenous Pfs230-Pfs48/45 complex. We show that Pfs48/45 interacts with domains 13 14, not included in current immunogens. Using transgenic parasite line domain to 14 deletion, these essential for localization on gamete surface....
Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed prostate, lung, cancers. However, little known about PSKH1 regulatory mechanisms, leading to its classification “dark” kinase. Here, we used biochemistry mass spectrometry define PSKH1’s consensus substrate motif, protein interactors, how including Ca 2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of canonical Calmodulin binding...
Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson’s Disease, but how is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human an endogenous array TOM and VDAC complexes. Symmetric arrangement two core around central VDAC2 dimer facilitated by TOM5 TOM20, both which also bind C-lobes. enters mitochondria through proximal TOM40 barrel complex, guided...
The calcium-calmodulin–dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It known to be activated by increases in intracellular Ca2+, but the mechanisms which it inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, metabolic derangements induced high-fat diet; therefore, elucidating that inactivate has important therapeutic implications. Here we show stimulation cAMP-dependent A...
Abstract PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate molecular details of interactions adapter CrkII Grb2 scaffold protein 14-3-3. Our findings rationalize why dimerization has a crucial function signal transduction provide biophysical structural data unravel binding...
Glycogen is a major energy reserve in liver and skeletal muscle. The master metabolic regulator AMP-activated protein kinase (AMPK) associates with glycogen via its regulatory β subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding homeostasis has not been investigated vivo. This study aimed to determine consequences disrupting interactions.Glycogen was disrupted mice whole-body knock-in (KI) mutation either AMPK β1 (W100A) or β2 (W98A) isoform...
Abstract The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. precise mechanism the terminal steps pathway, where RIPK3 kinase phosphorylates triggers conformation change oligomerization effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation MLKL activation loop as cue for pseudokinase domain dimerization. dimerization...
Abstract Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) initiating proliferation or differentiation. Here we characterise murine Tpo:TpoR signalling complex biochemically structurally, using cryo-electron microscopy. uses opposing surfaces to recruit two copies receptor, forming 1:2 complex. Although it binds same,...
Abstract Mutations that reduce expression or give rise to a Thr85Ser (T85S) mutation of Ca 2+ -CaM-dependent protein kinase kinase-2 (CaMKK2) have been implicated in behavioural disorders such as anxiety, bipolar and schizophrenia humans. Here we report Thr85 is an autophosphorylation site endows CaMKK2 with molecular memory enables sustained autonomous activation following initial, transient signal. Conversely, Ser85 the T85S mutant fails generate activity but instead causes partial loss...
ABSTRACT Calmodulin (CaM) serves an essential role in eukaryotic cells as a Ca 2+ sensor. binding leads to conformation changes CaM that enable engagement of repertoire enzymes and the regulation their catalytic activities. Classically, -CaM binds inhibitory pseudosubstrate sequence C-terminal kinase domain members dependent protein (CAMK) family, relieves inhibition promote activity. Here, we report unexpected mechanism by which can bind CHK2 inhibit its Using biochemical, biophysical,...
Abstract The Ca 2+ -calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity strongly associated with prostate hepatic cancers, whereas reduced has been linked to schizophrenia bipolar disease in humans. Here we report the functional effects nine rare-variant point mutations that were detected large-scale human genetic studies cancer tissues, all which occur close two regulatory phosphorylation...
EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators contact-dependent cell-cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, deregulation is strongly linked proliferative diseases. However, unlike receptors, whose catalytic activities thought initiate an signalling cascade, classified catalytically dead, raising question how non-catalytic functions...
Abstract Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of frequently phosphorylated damage, promotes cancer progression, but its role remains unclear. Here, we report molecular characterisation full-length, demonstrating preference for binding open functioning as sliding clamp. We identified phosphate interacting motif within CTD that dictates ATP hydrolysis...
Abstract WNK family kinases are regulated by osmotic stress and control ion homeostasis activating SPAK OXSR1 kinases. Using a proximity ligation approach, we found that promotes the association of WNK1 with NRBP1 pseudokinase TSC22D2/4 adaptor proteins. is closely related to isoforms also contains RΦ-motif binding conserved C-terminal (CCT) domain, similar CCT domains in WNKs, OXSR1. Knockdown markedly inhibited sorbitol-induced activation downstream components. AlphaFold-3 modelling...