The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress
Biochem J. 2024 Feb 21;481(4):265-278. doi: 10.1042/BCJ20230492.ABSTRACTThe identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to ...
Source: The Biochemical Journal - February 1, 2024 Category: Biochemistry Authors: Katy R McCarron Hannah Elcocks Heather Mortiboys Sylvie Urb é Michael J Clague Source Type: research
The mTORC2 signaling network: targets and cross-talks
Biochem J. 2024 Jan 25;481(2):45-91. doi: 10.1042/BCJ20220325.ABSTRACTThe mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex...
Source: The Biochemical Journal - January 25, 2024 Category: Biochemistry Authors: Aparna Ragupathi Christian Kim Estela Jacinto Source Type: research
Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism
Biochem J. 2024 Feb 21;481(4):191-218. doi: 10.1042/BCJ20230369.ABSTRACTInsulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature ...
Source: The Biochemical Journal - January 15, 2024 Category: Biochemistry Authors: Mehmood Ali Tripti Kumari Arvind Gupta Sariyah Akhtar Rahul Dev Verma Jimut Kanti Ghosh Source Type: research
Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome
Biochem J. 2024 Jan 9:BCJ20230319. doi: 10.1042/BCJ20230319. Online ahead of print.ABSTRACTCysteine string protein α (CSPα), also known as DNAJC5, is a member of the DnaJ/Hsp40 family of co-chaperones. The name derives from a cysteine-rich domain, palmitoylation of which enables localization to intracellular membranes, notably neuronal synaptic vesicles. Mutations in the DNAJC5 gene that encodes CSPα cause autosomal dominant, adult-onset neuronal ceroid lipofuscinosis (ANCL), a rare neurodegenerative disease. As null mutations in CSP-encoding genes in flies, worms and mice similarly result in neurodegeneration, CSP is e...
Source: The Biochemical Journal - January 9, 2024 Category: Biochemistry Authors: Eleanor Barker Amy Milburn Nordine Helassa Dean Hammond Natalia Sanchez-Soriano Alan Morgan Jeff Barclay Source Type: research
Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome
Biochem J. 2024 Jan 9:BCJ20230319. doi: 10.1042/BCJ20230319. Online ahead of print.ABSTRACTCysteine string protein α (CSPα), also known as DNAJC5, is a member of the DnaJ/Hsp40 family of co-chaperones. The name derives from a cysteine-rich domain, palmitoylation of which enables localization to intracellular membranes, notably neuronal synaptic vesicles. Mutations in the DNAJC5 gene that encodes CSPα cause autosomal dominant, adult-onset neuronal ceroid lipofuscinosis (ANCL), a rare neurodegenerative disease. As null mutations in CSP-encoding genes in flies, worms and mice similarly result in neurodegeneration, CSP is e...
Source: The Biochemical Journal - January 9, 2024 Category: Biochemistry Authors: Eleanor Barker Amy Milburn Nordine Helassa Dean Hammond Natalia Sanchez-Soriano Alan Morgan Jeff Barclay Source Type: research
Pseudouridylation-mediated gene expression modulation
Biochem J. 2024 Jan 10;481(1):1-16. doi: 10.1042/BCJ20230096.ABSTRACTRNA-guided pseudouridylation, a widespread post-transcriptional RNA modification, has recently gained recognition for its role in cellular processes such as pre-mRNA splicing and the modulation of premature termination codon (PTC) readthrough. This review provides insights into its mechanisms, functions, and potential therapeutic applications. It examines the mechanisms governing RNA-guided pseudouridylation, emphasizing the roles of guide RNAs and pseudouridine synthases in catalyzing uridine-to-pseudouridine conversion. A key focus is the impact of RNA-...
Source: The Biochemical Journal - January 4, 2024 Category: Biochemistry Authors: Jonathan L Chen W-Matthias Leeder Pedro Morais Hironori Adachi Yi-Tao Yu Source Type: research
Pseudouridylation-mediated gene expression modulation
Biochem J. 2024 Jan 10;481(1):1-16. doi: 10.1042/BCJ20230096.ABSTRACTRNA-guided pseudouridylation, a widespread post-transcriptional RNA modification, has recently gained recognition for its role in cellular processes such as pre-mRNA splicing and the modulation of premature termination codon (PTC) readthrough. This review provides insights into its mechanisms, functions, and potential therapeutic applications. It examines the mechanisms governing RNA-guided pseudouridylation, emphasizing the roles of guide RNAs and pseudouridine synthases in catalyzing uridine-to-pseudouridine conversion. A key focus is the impact of RNA-...
Source: The Biochemical Journal - January 4, 2024 Category: Biochemistry Authors: Jonathan L Chen W-Matthias Leeder Pedro Morais Hironori Adachi Yi-Tao Yu Source Type: research
Pseudouridylation-mediated gene expression modulation
Biochem J. 2024 Jan 10;481(1):1-16. doi: 10.1042/BCJ20230096.ABSTRACTRNA-guided pseudouridylation, a widespread post-transcriptional RNA modification, has recently gained recognition for its role in cellular processes such as pre-mRNA splicing and the modulation of premature termination codon (PTC) readthrough. This review provides insights into its mechanisms, functions, and potential therapeutic applications. It examines the mechanisms governing RNA-guided pseudouridylation, emphasizing the roles of guide RNAs and pseudouridine synthases in catalyzing uridine-to-pseudouridine conversion. A key focus is the impact of RNA-...
Source: The Biochemical Journal - January 4, 2024 Category: Biochemistry Authors: Jonathan L Chen W-Matthias Leeder Pedro Morais Hironori Adachi Yi-Tao Yu Source Type: research
Pseudouridylation-mediated gene expression modulation
Biochem J. 2024 Jan 10;481(1):1-16. doi: 10.1042/BCJ20230096.ABSTRACTRNA-guided pseudouridylation, a widespread post-transcriptional RNA modification, has recently gained recognition for its role in cellular processes such as pre-mRNA splicing and the modulation of premature termination codon (PTC) readthrough. This review provides insights into its mechanisms, functions, and potential therapeutic applications. It examines the mechanisms governing RNA-guided pseudouridylation, emphasizing the roles of guide RNAs and pseudouridine synthases in catalyzing uridine-to-pseudouridine conversion. A key focus is the impact of RNA-...
Source: The Biochemical Journal - January 4, 2024 Category: Biochemistry Authors: Jonathan L Chen W-Matthias Leeder Pedro Morais Hironori Adachi Yi-Tao Yu Source Type: research
The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography
Biochem J. 2024 Jan 2:BCJ20230450. doi: 10.1042/BCJ20230450. Online ahead of print.ABSTRACTMitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interfac...
Source: The Biochemical Journal - January 2, 2024 Category: Biochemistry Authors: Emma Buzzard Mathew McLaren Piotr Bragoszewski Andrea Brancaccio Holly Ford Bertram Daum Patricia Kuwabara Ian Collinson Vicki Gold Source Type: research
The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography
Biochem J. 2024 Jan 2:BCJ20230450. doi: 10.1042/BCJ20230450. Online ahead of print.ABSTRACTMitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interfac...
Source: The Biochemical Journal - January 2, 2024 Category: Biochemistry Authors: Emma Buzzard Mathew McLaren Piotr Bragoszewski Andrea Brancaccio Holly Ford Bertram Daum Patricia Kuwabara Ian Collinson Vicki Gold Source Type: research
The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography
Biochem J. 2024 Jan 2:BCJ20230450. doi: 10.1042/BCJ20230450. Online ahead of print.ABSTRACTMitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interfac...
Source: The Biochemical Journal - January 2, 2024 Category: Biochemistry Authors: Emma Buzzard Mathew McLaren Piotr Bragoszewski Andrea Brancaccio Holly Ford Bertram Daum Patricia Kuwabara Ian Collinson Vicki Gold Source Type: research
Non-crosslinking advanced glycation end products affect prohormone processing
Biochem J. 2023 Dec 19:BCJ20230321. doi: 10.1042/BCJ20230321. Online ahead of print.ABSTRACTAdvanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids. and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones. First, we employed solid phase peptide synthesis to generate unmodified as well as AGE-modified protease su...
Source: The Biochemical Journal - December 19, 2023 Category: Biochemistry Authors: Sebastian Brings Walter Mier Barbro Beijer Elisabeth Kliemank Stephan Herzig Julia Szendroedi Peter Nawroth Thomas Fleming Source Type: research
Non-crosslinking advanced glycation end products affect prohormone processing
Biochem J. 2023 Dec 19:BCJ20230321. doi: 10.1042/BCJ20230321. Online ahead of print.ABSTRACTAdvanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids. and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones. First, we employed solid phase peptide synthesis to generate unmodified as well as AGE-modified protease su...
Source: The Biochemical Journal - December 19, 2023 Category: Biochemistry Authors: Sebastian Brings Walter Mier Barbro Beijer Elisabeth Kliemank Stephan Herzig Julia Szendroedi Peter Nawroth Thomas Fleming Source Type: research
Non-crosslinking advanced glycation end products affect prohormone processing
Biochem J. 2023 Dec 19:BCJ20230321. doi: 10.1042/BCJ20230321. Online ahead of print.ABSTRACTAdvanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids. and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones. First, we employed solid phase peptide synthesis to generate unmodified as well as AGE-modified protease su...
Source: The Biochemical Journal - December 19, 2023 Category: Biochemistry Authors: Sebastian Brings Walter Mier Barbro Beijer Elisabeth Kliemank Stephan Herzig Julia Szendroedi Peter Nawroth Thomas Fleming Source Type: research
