Biology subjects

Dehury, B.

Publications and source records attributed to Dehury, B..

4 recordsLinked to original sources

bioRxiv2026

Homozygous c.820G>A variant in MGME1 contributes to multi-systemic mitochondrial dysfunction in an Indian patient cohort

Mitochondrial DNA (mtDNA) maintenance disorders arise from defects in mtDNA replication or repair, frequently resulting in extensive deletions or depletion of mtDNA. Mitochondrial genome maintenance exonuclease 1 (MGME1) is a nuclear-encoded nuclease essential for mtDNA replication and genome stability, and biallelic pathogenic variants in MGME1 cause mitochondrial DNA depletion syndrome 11. Here, we report a novel homozygous MGME1 missense variant c.820G>A (p. Ala274Thr) in five affected individuals from unrelated South Indian families presenting with proximal myopathy, chronic progressive external ophthalmoplegia, and cardiac and renal involvement. Patient-derived cells exhibited a significant reduction in mtDNA copy number, consistent with impaired mtDNA maintenance. Mechanistic analyses combining imaging-based and biochemical approaches demonstrated that the MGME1 variant disrupts both mtDNA replication and repair. Functional characterization further revealed defective oxidative phosphorylation and reduced mitochondrial membrane potential, confirming mitochondrial dysfunction. Collectively, our findings establish the pathogenicity of this novel MGME1 variant and expand the clinical and molecular spectrum of MGME1-associated mitochondrial disease, linking impaired mtDNA replication to multisystemic mitochondrial dysfunction. Graphical abstract summarySchematic overview of mitochondrial DNA (mtDNA) replication in wild-type and MGME1 mutant conditions. In wild-type cells, the coordinated activity of the mitochondrial replication machinery (TWNK, POLG, LIG3, TFAM, and MGME1) maintains mtDNA integrity and supports normal oxidative phosphorylation and ATP production. In contrast, the MGME1 mutation disrupts mtDNA replication and processing, leading to replication defects, mtDNA depletion, and mitochondrial dysfunction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/725852v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@406ce7org.highwire.dtl.DTLVardef@1adc863org.highwire.dtl.DTLVardef@3ef92aorg.highwire.dtl.DTLVardef@585559_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2024

Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in α-Synuclein Fibrils

Aberrant aggregation of -Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived -Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates -Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in -Synuclein fibrils. Here we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils. Subsequent in vitro studies and experiments in cells revealed that substitution of the two critical lysine residues K43 and K45 leads to a loss of all previously reported effects of polyP binding on -Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity. In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo -Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.

biophysics↗

bioRxiv2023

SERF2, an RNA G-quadruplex Binding Protein, promotes stress granule formation

Liquid-liquid phase transitions govern a wide range of protein-protein and protein-RNA interactions. Although the importance of multivalency and protein disorder in driving these transitions is clear, there is limited knowledge concerning the structural basis of phase transitions or the conformational changes that accompany this process. In this work, we found that a small human protein, SERF2, is important for the formation of stress granules. We determined the solution NMR structure ensemble of SERF2. We show that SERF2 specifically interacts with non-canonical tetrahelical RNA structures called G-quadruplexes, structures linked to stress granule formation. The biophysical amenability of both SERF2 and RNA G4 quadruplexes have allowed us to characterize the multivalent protein-RNA interactions involved in liquid-liquid phase transitions, the role that protein disorder plays in these transitions, identify the specific contacts involved, and describe how these interactions impact the structural dynamics of the components enabling a detailed understanding of the structural transitions involved in early stages of ribonucleoprotein condensate formation.

cell biology↗

bioRxiv2019

Membrane dynamics of Notch-bound γ-secretase produces two distinct Notch conformations

Cleavage of Notch by the major intramembrane aspartyl protease complex {gamma}-secretase is a central event in cell regulation and is also important to Alzheimers disease, with more than 200 mutations in the catalytic subunit of {gamma}-secretase (PS1) causing severe early-onset forms of the disease. Recently, cryogenic electron microscopy (cryo-EM) has revealed the electron density of the protein-Notch complex in frozen solution, indicating major changes upon substrate binding and a possible helix unwinding to expose peptide bonds. In order understand the all-atom dynamics that cause this process, and to test the Notch binding in a membrane protein rather than solution, we developed an all-atom model of mature wild-type {gamma}-secretase bound to Notch in a complete membrane-water system and studied the system using three independent 500-nanosecond molecular dynamics simulations. Our ensembles are in essential agreement with known cryo-EM data. As in previous simulations we find unusual {beta}-strand transitions in exposed parts of PS1. We also observe the atomic helix motions that cause loss of helicity in bound Notch by direct comparison to corresponding 500 ns simulations of free Notch, in particular five residues to the N-terminal site of the primary cleavage site. Most importantly, we identify three conformation states, with two of them differing in the Notch-bound catalytic site. These dynamics produce a ping-pong relationship of positioning the S3 cleavage sites of Notch relative to the aspartates. These conformation states are not visible in the cryo-EM data; probably the density is an average snapshot of the two states. Our identified conformation states rationalize how Notch cleavage can be imprecise and yield multiple products. Our identified conformation states may aid efforts to develop conformation-selective drugs that target C99 and Notch cleavage differently.\n\nStatement of SignificanceThe atomic dynamics underlying cleavage of Notch by {gamma}-secretase in the membrane is of major biological importance. Electron microscopy has revealed the protein-Notch complex in frozen solution, showing major changes upon substrate binding and helix unwinding to expose peptide bonds, but does not explain why substrate cleavage is imprecise and produces several products. Our model of wild-type {gamma}-secretase bound to Notch in a complete membrane-water system equilibrated by 3 x 500 nanoseconds of molecular dynamics strongly complements the electron microscopy data: We identify the specific loop and helix motions that cause the {beta}-strand transitions in PS1 and the loss of helicity in specific residues of bound Notch. We identify different conformations of Notch, which importantly affect the S3 cleavage site; the open state may cause the imprecise cleavage with earlier release of products. Our identified states can aid development of conformation-selective drugs that target C99 and Notch cleavage differently.

biophysics↗