Michael Silk's research while affiliated with University of Melbourne and other places

Publications (14)

Article
Full-text available
The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investiga...
Article
Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates includi...
Preprint
Full-text available
Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. While a number of genes have been successfully implicated, it remains challenging to identify causative mutations within these genes from the background variation present in all individuals due to disease...
Article
Full-text available
The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome sequences to over 81,000 experimental structures and homology models of the human proteome, we have calculated both regional intolerance to missense variation (Missense Tolerance Ratio, MTR), using a sliding window of 21–...
Chapter
Mutations in protein-coding regions can lead to large biological changes and are associated with genetic conditions, including cancers and Mendelian diseases, as well as drug resistance. Although whole genome and exome sequencing help to elucidate potential genotype–phenotype correlations, there is a large gap between the identification of new vari...
Article
The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms to inform effective vaccine and drug development. Despite the novelty of the virus, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implica...
Article
Full-text available
MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Hom...
Preprint
Full-text available
The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms, to inform effective vaccine and drug development. Despite viral novelty, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of S...
Article
Full-text available
EasyVS is a web-based platform built to simplify molecule library selection and virtual screening. With an intuitive interface, the tool allows users to go from selecting a protein target with a known structure and tailoring a purchasable molecule library to performing and visualising docking in a few clicks. Our system also allows users to filter...
Chapter
High-throughput computational techniques have become invaluable tools to help increase the overall success, process efficiency, and associated costs of drug development. By designing ligands tailored to specific protein structures in a disease of interest, an understanding of molecular interactions and ways to optimize them can be achieved prior to...
Article
Full-text available
Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present t...
Preprint
We have isolated a mouse strain with a single missense mutation in the gene encoding MLKL, the essential effector of necroptotic cell death. The resulting substitution lies within the two-helix brace and confers constitutive, RIPK3 independent, killing activity to MLKL. Mice homozygous for MlklD139V develop lethal inflammation within days of birth,...
Article
Full-text available
Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient...

Citations

... Features describing conservation and function, local residue environment, stability and dynamics, and protein interaction changes were calculated to account for protein properties. Conservationbased features included rate of residue evolution (ConSurf 26 ) and predictions of functional deleteriousness through MTR3D, 27 Polyphen-2, 28 PROVEAN, 29 SIFT 30 and SNAP2. 31 Local residue environment was characterised through backbone phi and psi angles, residue depth and relative solvent accessibility (RSA). ...
... In part to address this problem, several web-based tools have been developed to facilitate the study of SARS-CoV-2 spatiotemporal dynamics, mutational frequency, and/or threedimensional (3D) protein structure [19][20][21][22]. Though useful for gaining broad insights, these applications are often limited to analysis pre-determined datasets with minimal user control such as, COVIDCG [23], outbreak info [24], covariants [25], 2019nCoVR [26], CoV-GLUE [27] and COG-UK [28]. ...
... In part to address this problem, several web-based tools have been developed to facilitate the study of SARS-CoV-2 spatiotemporal dynamics, mutational frequency, and/or three-dimensional (3D) protein structures [19][20][21][22]. Though useful for gaining broad insights, these applications are often limited to the analysis of predetermined datasets with minimal user control, such as COVIDCG [23], outbreak info [24], covariants [25], 2019nCoVR [26], CoV-GLUE [27], and COG-UK [28]. ...
... Protein thermodynamic stability changes are associated with heritable diseases [1][2][3][4][5][6] and drug resistance [7][8][9][10][11]. Nearly-onethird of non-synonymous single-nucleotide variants (nsSNVs) are deleterious to human health [12]. ...
... Through this score, more conserved sites (having slower evolutionary rates), which have important functional and structural consequences are identified [106]. Consurf has been used to estimate and visualise conserved regions within SARS-CoV-2 [107], the SARS-CoV nsp12 polymerase domain [108], and T. Tunstall, S. Portelli, J. Phelan et al. ...
... The three-dimensional structures of the five proteins of EHP were used as targets for screening drugs from the ZINC15 [67] and ChEMBL [68] databases with docking-based VS using the EasyVS web-based VS tool (http://biosig.unimelb.edu.au/easyvs/ accessed on 25 January 2022) [69]. A sequential screening strategy was employed for screening the drug molecules. ...
... Genetic intolerance analysis has emerged as a powerful tool for studying protein evolution, structure-function relationships, and linkage of proteins to disease. [1][2][3][4][5][6][7][8][9][10] Here we examine an extreme form of protein sequential intolerance by identifying human proteins that contain segments in which genetic variation is completely disallowed by evolution. ...
... In addition, since PS exposure immediately follows MLKL activation and pMLKL is directly associated with the plasma membrane, MLKL might possess the ability to directly effect scramblase [102,117] (Fig. 2). In support, Mlkl D139V/D139V neonates, which carry a missense mutation results in spontaneously activated MLKL, were recently reported to demonstrate increased Annex-inV binding in some hematopoietic progenitor populations [118]. ...
... Since GRIN2A and GRIN2B are the two most prevalent forms of GRIN, a thorough analysis of these two sub-units offers a chance to comprehend the structural, functional, and genetic roots of the problems these patients are suffering from. [55] ...