A5069606823- Metabolism, Diabetes, and Cancer
- Growth Hormone and Insulin-like Growth Factors
- Pancreatic function and diabetes
- Oral microbiology and periodontitis research
- Protein Kinase Regulation and GTPase Signaling
- Cytomegalovirus and herpesvirus research
- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Immunodeficiency and Autoimmune Disorders
- Receptor Mechanisms and Signaling
- Advanced Proteomics Techniques and Applications
- Ubiquitin and proteasome pathways
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Diabetes Treatment and Management
- thermodynamics and calorimetric analyses
- Tuberculosis Research and Epidemiology
- Parasites and Host Interactions
- Glycosylation and Glycoproteins Research
- Advanced Fluorescence Microscopy Techniques
- Advanced biosensing and bioanalysis techniques
- Cellular transport and secretion
- Mycobacterium research and diagnosis
- Extracellular vesicles in disease
- Inflammasome and immune disorders
- Nanopore and Nanochannel Transport Studies
Walter and Eliza Hall Institute of Medical Research
2009-2024
University of Otago
2014
CSL (Australia)
2000-2002
Parks Victoria
2002
The Royal Melbourne Hospital
1998
Human type 1 insulin-like growth factor receptor is a homodimeric tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like binding understood to relax conformational restraints within the homodimer, initiating transphosphorylation of domains. However, no three-dimensional structures exist for ectodomain inform atomic-level understanding these events. Here, we present crystal apo...
Understanding the structural biology of insulin receptor and how it signals is key importance in development analogs to treat diabetes. We report here a cryo-electron microscopy structure single bound physiologically relevant, high-affinity version ectodomain, latter generated through attachment C-terminal leucine zipper elements overcome conformational flexibility associated with ectodomain truncation. The resolution maps 3.2 Å insulin-binding region 4.2 membrane-proximal region. reveals...
Monomers of the insulin receptor and type 1 insulin-like growth factor (IGF-1R) can combine stochastically to form heterodimeric hybrid receptors. These receptors display ligand binding signaling properties that differ from those homodimeric Here, we describe cryoelectron microscopy structure such a in complex with I (IGF-I). The (ca. 3.7 Å resolution) displays single IGF-I ligand, bound similar fashion seen for IGFs IGF-1R. engages first leucine-rich-repeat domain cysteine-rich region...
Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of I. Relatively little is known about role II signaling via IGF-1R, despite affinity for IGF-1R being within an order magnitude that Here, we describe cryoelectron microscopy structure bound a leucine-zipper-stabilized ectodomain, determined two conformations maximum average resolution 3.2 Å. The differ relative separation their respective points membrane entry, and comparison with I reveals...
Abstract The function and phenotype of γδ T cells in the context common variable immunodeficiency (CVID) has not been explored. CVID is a primary disorder characterized by impaired antibody responses resulting increased susceptibility to infections. are subset unconventional that play crucial roles host defence against In this study, we aim determine functions CVID. We observe higher frequency Vδ1 + compared healthy controls, particularly older patients. also find proportion effector-memory...
The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change the extracellular region that turn effects trans-activation of intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures show how 33-mer polypeptide unrelated to cross-link two sites on...
The C-terminal segment of the insulin receptor (IR) α-chain plays a critical role in binding. This 16-residue peptide together with central β-sheet L1 domain forms one binding surfaces IR monomer. Here we use isothermal titration calorimetry to assay directly αCT an construct (IR485) consisting three N-terminal domains Our measurements show further that IR485 competes prototypical "Site 1" mimetic same fragment. competitive nature their appears be reflected previously undetected sequence...
Background Common Variable Immunodeficiency (CVID) is classified as a ‘Predominantly Antibody Deficiency’ (PAD), but there emerging evidence of cellular immunodeficiency in subset patients. This includes CVID patients diagnosed with cytomegalovirus (CMV) infection, hallmark ‘combined immunodeficiency’. CMV infection also has the potential to drive immune dysregulation contributing significant morbidity and mortality CVID. We aim determine extent dysfunction patients, whether this correlates...
We report the characterization of a Porphyromonas gingivalis gene, designated omp28, encoding protein that we have previously purified and characterized as 28-kDa outer membrane protein. The deduced amino acid sequence omp28 open reading frame displayed an leader lipoprotein attachment site but did not exhibit any significant overall identity with sequences in databases. A small stretch acids (19 residues) exhibits 50% segment fimbrial from Dichelobacter nodosus involved adhesion, suggesting...
Abstract Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial constantly exposed to a variety molecular factors and shear force that can induce cellular damage stress. However, how removed or eliminate unwanted contents, remains unclear. The generation large extracellular vesicles (EVs) has emerged as key mechanism for removal waste from dying stressed. Here, we used intravital microscopy bone marrow directly...
Abstract Purpose The COVID PROFILE cohort is a longitudinal clinical study based in Victoria Australia, which was established to understand immunity SARS-CoV-2 low transmission population setting and identify immunological markers of long-term immune-dysregulation after both infection vaccination. Additionally, this as biobank resource for researchers address other health-related questions. Participants We enrolled 178 adult community members, including household contacts, who had either...
A range of fusion constructs (expressed in Escherichia coli) were produced that contained two or more HPV6b E proteins, producing a single continuous amino acid sequence corresponding to the sequences individual proteins. The also included C-terminal hexahistidine tag fused in-frame aid purification. proteins (polyproteins) semipurified by Ni(++) metal affinity chromatography under denaturing conditions. Immunization BALB/c mice with these polyproteins resulted production specific protein...
MicrosymposiaC146 binds to a groove of tetrameric GAPDH, while N-terminal region CP12 is largely unstructured.We also observed that the dimeric PRK adopts distinct conformations generated by rigid body movement protomer, suggesting exists in equilibrium between solution.Together with mutagenesis analysis, these data demonstrated partially folded on binding first target and part within GAPDH-CP12 complex plays crucial role selective interaction specific conformer from possible conformational...