Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein’s precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child’s clinical presentation

Control of Ras/Erk signalling pathway by the brahma chromatin-remodelling complex.

The SWI/SNF complex is a large, multi subunit chromatin-remodelling transcriptional regulator complex with an ATPase subunit, Brahma. Recently published data from our laboratory has revealed that Brahma regulates the activity of the EGFR signalling pathway in Drosophila. The study presented here was conducted to further elucidate which components of the EGFR/Ras/Raf/Erk pathway are regulated by Brahma, and also the mechanism behind this regulation. Analysis of components in this pathway at both the transcriptional and protein levels following overexpression of wild-type Brahma in Drosophila S2 cells, demonstrated that Brahma may affect EGFR mRNA expression and Ras protein level. In addition, previous studies suggest that Brahma activity is regulated through phosphorylation by kinases, including Erk and cyclin E/CDK 2. Analysis of Brahma immunoprecipitated from S2 cells by mass spectrometry revealed contamination by Myosin. Ion exchange chromatography and ammonium sulphate precipitation were used to separate Brahma from Myosin for phosphorylation site analysis by mass spectrometry.Bachelor of Science in Biological Science

Mechanisms of Generating Polyubiquitin Chains of Different Topology

Ubiquitination is an important post-translational process involving attachment of the ubiquitin molecule to lysine residue/s on a substrate protein or on another ubiquitin molecule, leading to the formation of protein mono-, multi- or polyubiquitination. Protein ubiquitination requires a cascade of three enzymes, where the interplay between different ubiquitin-conjugating and ubiquitin-ligase enzymes generates diverse ubiquitinated proteins topologies. Structurally diverse ubiquitin conjugates are recognized by specific proteins with ubiquitin-binding domains (UBDs) to target the substrate proteins of different pathways. The mechanism/s for generating the different ubiquitinated proteins topologies is not well understood. Here, we will discuss our current understanding of the mechanisms underpinning the generation of mono- or polyubiquitinated substrates. In addition, we will discuss how linkage-specific polyubiquitin chains through lysines-11, -48 or -63 are formed to target proteins to different fates by binding specific UBD proteins