The FEBS journal最新文献

{"title":"KU80 suppresses endonuclease G activity to preserve genomic integrity","authors":"Jargalan Batsaikhan,&nbsp;Kwang-Hyun Park,&nbsp;Hae Ryung Chang,&nbsp;Eunyoung Jung,&nbsp;Myung-Jin Kim,&nbsp;Jeeyoon Kang,&nbsp;Hyunjo Shim,&nbsp;Eui-Jeon Woo,&nbsp;Yonghwan Kim","doi":"10.1111/febs.70495","DOIUrl":"10.1111/febs.70495","url":null,"abstract":"<p>Endonuclease G (ENDOG) is involved in DNA replication, mitochondrial DNA maintenance, and late apoptosis. Its role in genome maintenance and cell death necessitates strict regulation to prevent unwanted DNA damage. Although inhibitors of ENDOG have been identified in nonmammalian species, no such inhibitors have been discovered in mammals. Here, we identify KU80 as a novel negative regulator of ENDOG in human cells. The KU80 C-terminal domain (CTD) shares structural homology with <i>Drosophila</i> EndoG inhibitor (EGI), directly binds ENDOG and inhibits its nuclease activity <i>in vitro</i>. <i>In silico</i> modeling and immunoprecipitation reveal the KU80 core domain mediates ENDOG interaction. Depletion of KU80 increases nuclear ENDOG accumulation and DNA damage under normal conditions, evidenced by elevated phosphorylated histone H2AX (γH2AX) levels. Conversely, ENDOG-deficient cells show reduced DNA damage and increased chemotherapeutic resistance. We uncover a mechanism where KU80 maintains genomic stability by inhibiting ENDOG activity and nuclear translocation. This study establishes KU80 as a key DNA damage response regulator, offering insights into potential therapies for diseases linked to dysregulated ENDOG activity.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5952-5966"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of cation-π interactions using quantum chemistry and statistical analysis of high-resolution protein structures.","authors":"Hessel Poelman, Jochen Eeckhoudt, Kanin Wichapong, Gert Vriend, Esther Lutgens, Mercedes Alonso, Gerry A F Nicolaes","doi":"10.1111/febs.70750","DOIUrl":"https://doi.org/10.1111/febs.70750","url":null,"abstract":"<p><p>Cation-π interactions are widely considered key contributors to protein structure and molecular recognition, with quantum chemical studies often predicting substantial stabilization energies. However, their actual prevalence and strength in protein environments remain debated. Here, we combine high-level quantum chemical calculations with large-scale statistical analyses of high-resolution protein structures to reassess the role of lysine-π interactions. While gas-phase calculations confirm strong cation-π binding for idealized geometries, with corresponding energies of -19.0 kcal·mol^-1 and -16.0 kcal·mol^-1 for Lys-Phe and Arg-Phe pairs respectively, we demonstrate that even small geometric distortions and the inclusion of dielectric screening significantly reduce interaction energies to respective values of -5.9 kcal·mol^-1 and -6.5 kcal·mol^-1 at a dielectric constant of 6 and to -3.7 kcal·mol^-1 and -4.7 kcal·mol^-1 at a dielectric constant of 78. By leveraging the current size of the Protein Data Bank, we analyzed a much larger set of high-resolution protein structures than previously feasible, enabling a more rigorous evaluation of the structural prevalence of lysine-π interactions. Our statistical analysis reveals a low occurrence of geometries consistent with optimal cation-π interactions. By bridging quantum chemical results with structural data, this work reconciles the discrepancy between strong intrinsic interaction energies and their limited manifestation in proteins. These findings highlight the importance of geometric and environmental effects and suggest that Lys-π interactions in proteins are context-dependent and likely contribute less to protein structure than previously assumed.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A distinct gene expression mechanism for d-amino acid utilization in hyperthermophilic archaeon Pyrococcus horikoshii","authors":"Ryushi Kawakami,&nbsp;Tomoki Kawase,&nbsp;Taira Uehara,&nbsp;Haruhiko Sakuraba,&nbsp;Tomohiko Matsuzawa,&nbsp;Junji Hayashi,&nbsp;Toshihisa Ohshima","doi":"10.1111/febs.70545","DOIUrl":"10.1111/febs.70545","url":null,"abstract":"<p>Growing the hyperthermophilic archaeon <i>Pyrococcus horikoshii</i> OT-3 in medium supplemented with <span>d</span>-<i>allo</i>-Ile instead of <span>l</span>-Ile markedly upregulates the activity of broad substrate specificity amino acid racemase (BAR). In <i>P. horikoshii</i> genome, the BAR gene (<i>PH0138</i>) forms a cluster with <i>PH0137</i>, which encodes a putative transporter protein, and <i>PH0140</i> that encodes a feast/famine regulatory protein (FFRP), involved in the transcriptional regulation of metabolic pathway genes. Here, we performed gene expression, protein–DNA interaction, and crystallographic analyses to elucidate the expression mechanism of the BAR cluster. Gene expression analysis revealed that <span>d</span>-<i>allo</i>-Ile simultaneously induces <i>PH0138</i> and <i>PH0137</i>. Electrophoretic mobility shift assays demonstrated that the PH0140 protein binds to the <i>PH0137</i> promoter in the presence of <span>l</span>-Ile, but this interaction is disrupted by <span>d</span>-<i>allo</i>-Ile, identifying PH0140 as a <span>d</span>-amino acid-responsive regulatory protein (DARP). The crystal structures of DARP bound to <span>l</span>-Ile and <span>d</span>-<i>allo</i>-Ile were compared with those of another FFRP family member, <i>P. horikoshii</i> FL11. Our findings reveal a dimeric arrangement of <span>l</span>-Ile-bound DARP resembling the DNA-bound (open) form of FL11, whereas <span>d</span>-<i>allo</i>-Ile-bound DARP corresponds to the DNA-unbound (closed) form. These conformational changes result from subtle alterations in hydrogen bonding around the coregulators. Furthermore, cultivation in <span>d</span>-<i>allo</i>-Ile substitution medium only impacted the expression of <i>PH0138</i> and <i>PH0137</i>, and not the other genes, suggesting that DARP regulates a more limited gene set than FL11. Cumulatively, these results reveal a distinct mechanism by which an FFRP homolog controls <span>d</span>-amino acid utilization.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5881-5897"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147701021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N-terminal segment of the human ANKZF1 negatively regulates its internal mitochondrial targeting signal to prevent localization to mitochondria","authors":"Mudassar Ali,&nbsp;Bhoopesh Maheswaran,&nbsp;Devid Sahu,&nbsp;Nidhi Malhotra,&nbsp;Koyeli Mapa","doi":"10.1111/febs.70526","DOIUrl":"10.1111/febs.70526","url":null,"abstract":"<p>ANKZF1, the mammalian ortholog of yeast Vms1, is a multidomain cytosolic protein. Occasionally, the protein is also found in mitochondria, although the reason for its mitochondrial localization and the mechanism of its mitochondrial targeting remain unclear. Despite the absence of any predicted mitochondrial targeting sequence or domain (MTS/MTD) in the protein, ANKZF1 possesses multiple internal matrix-targeting sequence-like sequences (iMTS-Ls). In this study, we demonstrate that the N-terminal 73 residues of ANKZF1 negatively regulate its mitochondrial targeting, and this portion of the protein is sufficient to hinder mitochondrial targeting of Δ73-ANKZF1 upon co-expression. Using a series of truncation mutants of ANKZF1, we further demonstrate that the iMTS-Ls comprised of residues 231–240 of ANKZF1 are essential for its mitochondrial localization. Furthermore, the sequence of this region is well conserved across different organisms, indicating the structural and functional importance and role in maintaining the mitochondrial targeting of the protein. Importantly, residues 231–324 of ANKZF1 form two consecutive predicted iMTS-Ls, which together constitute an independent mitochondrial signal sequence that can target green fluorescent protein (GFP) to the mitochondria when fused to the N terminus. Furthermore, by molecular dynamics simulation, we show that the deletion of the N-terminal 74 amino acids of ANKZF1 leads to a massive structural rearrangement within the protein, causing the opening of its C-terminal part and solvent exposure of the 231–240 residues. We postulate that these structural rearrangements and exposure of the internal MTS in the absence of the N-terminal segment of ANKZF1 lead to its mitochondrial translocation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5735-5758"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UbiB proteins mediate an ATP-dependent decarboxylation step in bacterial ubiquinone biosynthesis.","authors":"Katayoun Kazemzadeh, Bruno Faivre, Sophie-Carole Chobert, Martial Rey, Sophie S Abby, Julie Michaud, Tuan-Anh Dinh, Alexandre Chilin, Olivier Lerouxel, Marc Fontecave, Fabien Pierrel, Murielle Lombard, Ludovic Pelosi","doi":"10.1111/febs.70749","DOIUrl":"https://doi.org/10.1111/febs.70749","url":null,"abstract":"<p><p>Polyisoprenoid quinones such as ubiquinone (UQ) play an essential role in cellular physiology, acting as membrane-bound electron and proton carriers in respiratory chains and other biological processes across all domains of life. In Escherichia coli, the canonical UQ biosynthesis pathway is well characterized. It involves 12 proteins (UbiA-UbiK and UbiX), most of which catalyze one of the eight modifications of the aromatic ring derived from 4-hydroxybenzoic acid (4-HB), while others (UbiB, UbiJ, UbiK) act as accessory factors ensuring efficient UQ production. Following prenylation by UbiA and subsequent decarboxylation by the UbiX/UbiD system, the final six reactions are catalyzed within a soluble Ubi-complex. UbiB, an atypical protein kinase-like enzyme, was proposed to extract decarboxylated intermediates from the membrane and mediate their delivery to the Ubi-complex. In this study, we demonstrate the existence of an alternative decarboxylation system in E. coli, as UQ biosynthesis can proceed in the absence of the UbiX/UbiD system. Our results show that this alternative decarboxylation activity depends on UbiB and requires its adenosine triphosphatase activity. Bioinformatic analyses further revealed that approximately 27% of Pseudomonadota species lack UbiX/UbiD homologs, and we found that UbiB proteins from two such species enhance the alternative decarboxylation activity when expressed in E. coli. In addition, we identified conserved residues in UbiB that are specifically required for decarboxylation but dispensable for the delivery of UQ intermediates to the Ubi-complex. Taken together, our findings support a model in which UbiB acts as an ATP-dependent decarboxylase, thereby broadening the functional scope of this poorly characterized protein.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of 42 CK2α de novo variants associated with Okur-Chung neurodevelopmental syndrome","authors":"Alexander Gast,&nbsp;Christian Werner,&nbsp;Karsten Niefind,&nbsp;Joachim Jose","doi":"10.1111/febs.70538","DOIUrl":"10.1111/febs.70538","url":null,"abstract":"<p>In 2016, <i>CSNK2A1</i>, the gene which encodes the catalytic α-subunit of human protein kinase CK2 was linked to an autism spectrum disorder called Okur-Chung neurodevelopmental syndrome (OCNDS) for the first time. Human protein kinase CK2 is a heterotetrameric phosphotransferase with an α₂β₂ composition. To gain more insight into genotype–phenotype relationships, 42 CK2α variants associated with OCNDS were characterized in this study in terms of enzymatic activity using a canonical CK2 peptide substrate. Out of the 42 variants tested, 13 had no detectable enzymatic activity and 12 showed less than 10% of wild-type CK2α activity. The addition of the regulatory CK2β subunit increased the activity of all active variants. Twelve variants that exhibited at least 30% wild-type enzymatic activity were chosen to determine the dissociation constants with CK2β; highlighting that none of these mutations had an impact on the interaction of CK2α with CK2β. The variants R21Q, T127M, E264D, E282K, and R333* showed no reduced activity in comparison to wild-type CK2α. Additionally, affinity to CK2β and thermostability remained unaltered. K198R is the most frequent missense variant observed in OCNDS patients; thus, we performed a site-saturation mutagenesis at position K198 to elucidate what impact other variants at this position could have on enzymatic activity. Results showed that replacement of K198 by any other amino acid resulted in similar loss of activity as the prevalent K198R variant. The presented results suggest that other parameters beyond enzymatic activity, CK2β affinity or thermostability may contribute to neurodevelopmental disorders such as OCNDS.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5759-5779"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bringing cellular clarity to the cortical component of ALS with a high-density multi-electrode array system","authors":"Zehra Yagmur Erol,&nbsp;Christopher Quintanilla,&nbsp;P. Hande Ozdinler","doi":"10.1111/febs.70552","DOIUrl":"10.1111/febs.70552","url":null,"abstract":"<p>There is selective vulnerability in diseases, requiring the understanding of cell-type specific aspects of neurodegeneration with cellular resolution. Single-cell electrophysiology enables direct investigation of neuronal excitability, ion-channel dynamics, and synaptic transmission with high temporal precision, which is crucial in understanding neuronal circuitries and how they are affected in diseases. Microelectrode arrays (MEAs) have emerged as powerful platforms enabling long-term, parallel, and non-invasive extracellular measurements. The advent of complementary-metal-oxide-semiconductor (CMOS)-based and high-density microelectrode arrays (HD-MEAs) has expanded the spatial and temporal resolution attainable both in vitro and ex vivo. Combined with acute slices, novel cell-culture approaches and three-dimensional (3D) brain organoids, these tools now expedite translational research in disease modeling, neurotoxicity, and pharmacology. Here, we summarise the significance of single-cell electrophysiology, the advantages of the MEA systems, and the latest biomedical and technological advances in this area of research.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5686-5695"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70552","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Slm1, an F-BAR and PH domain-containing protein, regulates heat-induced turnover of nutrient transporter to control plasma-membrane quality","authors":"Ken-taro Sakata,&nbsp;Keisuke Hashii,&nbsp;Kaori Yae,&nbsp;Ryohei Tsuda,&nbsp;Yeyangguang He,&nbsp;Nao Komatsu,&nbsp;Rina Shirai,&nbsp;Ayane Nagai,&nbsp;Tatsuya Maeda,&nbsp;Naotaka Tanaka,&nbsp;Mitsuaki Tabuchi","doi":"10.1111/febs.70540","DOIUrl":"10.1111/febs.70540","url":null,"abstract":"<p>Cells must rapidly reorganize plasma membrane (PM) architecture to withstand heat stress, yet how PM quality control (PMQC) is coordinated with stress-activated signaling pathways remains poorly understood. In budding yeast, heat stress activates both the cell wall integrity (CWI) pathway and PMQC: the former repairs cell wall damage through the Rho1-Pkc1-MAPK cascade, whereas the latter removes heat-damaged amino acid-polyamine-organocation (APC) transporters via ubiquitin-dependent endocytosis. Eisosomes are PM invaginations that harbor multiple APC transporters together with the F-BAR- and PH-domain-containing proteins Slm1/Slm2, which upon stress relocalize to TORC2-containing domains to promote sphingolipid synthesis. Although Slm proteins participate in stress adaptation, how the abundance of Slm proteins affects PMQC is unknown. To address this question, we engineered a Tet-off strain that enables controlled expression of GFP-tagged Slm1 (GFP-Slm1) and found that Slm1 is massively overexpressed (~ 48-fold) in the absence of doxycycline. GFP-Slm1 overexpression caused strong temperature and canavanine sensitivity and produced abnormal cortical actin organization together with defective recycling of PM proteins, including the v-SNARE Snc1. Notably, these actin and trafficking defects were further exacerbated in eisosome-deficient cells, where excess GFP-Slm1 redistributed broadly along the PM and formed prominent membrane-associated aggregates. Under heat stress, excess Slm1 selectively delays the endocytic turnover and vacuolar degradation of heat-damaged APC transporters, leading to their prolonged accumulation at the PM. Together, our findings identify Slm1 as a regulator of PMQC that modulates the heat-induced turnover of nutrient transporters and other PM proteins and reveal that eisosome function buffers against Slm1-driven defects in actin-dependent membrane trafficking.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5859-5880"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatially resolved mapping of histones reveals selective neuronal response in Rett syndrome","authors":"Frederike Schäfer,&nbsp;Giuseppina De Rocco,&nbsp;Moritz Völker-Albert,&nbsp;Ignasi Forne,&nbsp;Nicoletta Landsberger,&nbsp;Axel Imhof,&nbsp;Shibojyoti Lahiri","doi":"10.1111/febs.70534","DOIUrl":"10.1111/febs.70534","url":null,"abstract":"<p>Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked <i>Mecp2</i> gene, results in profound life-long neurological dysfunction. Rett syndrome patients live an apparently normal initial life until 12–18 months of age, after which a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC–MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wild-type (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutation. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in Rett syndrome and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of Rett syndrome and emphasize the importance of personalized therapeutic strategies that consider both the affected cell type and particular Mecp2 mutation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5814-5836"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PACS-1 unlocked: How a single mutation disrupts intramolecular regulation to drive neurodevelopmental disease","authors":"Nadia Izadi-Pruneyre","doi":"10.1111/febs.70613","DOIUrl":"10.1111/febs.70613","url":null,"abstract":"<p>Rare monogenic disorders provide powerful insights into fundamental cell biology. PACS1 syndrome is a striking example of this: a neurodevelopmental disorder, caused almost exclusively by a single missense mutation in the <i>PACS1</i> gene (c.607C&gt;T), resulting in the Arg203Trp (R203W) amino-acid substitution. Despite the relative genetic simplicity, the exact molecular mechanism through which this mutation drives disease remains unknown. In their study published in this issue of <i>The FEBS Journal</i>, Krzysiak <i>et al.</i> provide a compelling mechanistic framework, demonstrating that the R203W substitution disrupts intramolecular regulation of PACS-1, thereby impairing a critical signalling hub.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 19","pages":"5700-5702"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148267623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}