Journal of Biological Chemistry最新文献_第2页

Subcellular determinants of orthoflavivirus protease activity. 正黄病毒蛋白酶活性的亚细胞决定因素。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-04 DOI: 10.1016/j.jbc.2025.110451

Lochlain Corliss, Chad M Petit, Nicholas J Lennemann

{"title":"Subcellular determinants of orthoflavivirus protease activity.","authors":"Lochlain Corliss, Chad M Petit, Nicholas J Lennemann","doi":"10.1016/j.jbc.2025.110451","DOIUrl":"10.1016/j.jbc.2025.110451","url":null,"abstract":"Orthoflaviviruses are small, enveloped, positive-sense RNA viruses that cause over 500 million infections globally each year for which there are no antiviral treatments. The viral protease is an attractive target for therapeutics due to its critical functions throughout infection. Many studies have reported on the structure, function, and importance of orthoflavivirus proteases; however, the molecular determinants for cleavage of intracellular substrates by orthoflavivirus proteases and how these factors affect viral fitness are unknown. In this study, we used our fluorescent, protease-activity reporter system to investigate the subcellular determinants involved in orthoflavivirus protease cleavage. By modifying our reporter platform, we identified endoplasmic reticulum (ER) subdomain localization and membrane proximity of the substrate cleavage site as two previously uncharacterized molecular determinants for cleavage. We also altered the amino acid composition of the reporter recognition motif to introduce sequences present at the cytoplasmic cleavage junctions within orthoflavivirus polyproteins and found that each protease processed the sequence located at the junction between NS4A and the 2K peptide least efficiently. Live-cell imaging revealed that cleavage of the NS4A|2K motif is significantly delayed compared to the capsid cleavage sequence. We further determined that introducing a more efficient cleavage sequence into the NS4A|2K junctions of orthoflavivirus infectious clones abolished virus recovery. Overall, this study identifies ER subdomain localization and membrane proximity of the recognition motif as molecular determinants for cleavage by orthoflavivirus proteases and provides insight into the role that sequence specificity plays in the coordinated processing of the viral polyprotein and establishing productive infections.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110451"},"PeriodicalIF":4.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic regulation of Sec24C by phosphorylation and O-GlcNAcylation during cell cycle progression. 在细胞周期进程中，磷酸化和o - glcn酰化对Sec24C的动态调控。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110456

George R Georgiou, Tetsuya Hirata, Erik Soderblom, Rose Homoelle, Jakob Maiwald, Michael Boyce

{"title":"Dynamic regulation of Sec24C by phosphorylation and O-GlcNAcylation during cell cycle progression.","authors":"George R Georgiou, Tetsuya Hirata, Erik Soderblom, Rose Homoelle, Jakob Maiwald, Michael Boyce","doi":"10.1016/j.jbc.2025.110456","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110456","url":null,"abstract":"During mitosis, eukaryotic cells cease anterograde trafficking from the endoplasmic reticulum (ER) towards the Golgi. This cessation corresponds with the dispersal of the COPII transport protein, Sec24C, from juxtanuclear ER exit sites (ERES) into a diffusely cytosolic pool. Redistribution of Sec24 paralogs and other core COPII proteins may underlie the mitotic pause in secretion and may be required for the equal inheritance of endomembrane organelles and machinery by both daughter cells. Therefore, it is important to understand the mechanisms governing the mitotic relocalization of COPII components. Here, we explore the role of post-translational modifications (PTMs) of the model COPII protein Sec24C in this phenotypic switch during mitosis. In interphase, Sec24C is modified by O-linked β-N-acetylglucosamine (O-GlcNAc), and we show that this glycan is rapidly removed upon mitotic entry, influencing the timing of Sec24C dispersal. Additionally, we identify novel, cell cycle phase-enriched phosphorylation events on Sec24C, including phosphosites that regulate the stability and localization of the protein, providing the first systematic characterization of dynamic PTMs on any Sec24 protein. Together, our data support the hypothesis that phosphorylation and glycosylation of Sec24C act in concert to induce rapid dispersal upon mitotic entry and may promote equal partitioning of the endomembrane system to daughter cells after division.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110456"},"PeriodicalIF":4.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hsp110 Nucleotide Exchange Factors may amplify Hsp70-disaggregation by enhanced entropic pulling. Hsp110核苷酸交换因子可能通过增强熵拉来放大hsp70的分解。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110450

Mathieu E Rebeaud,Bruno Fauvet,Paolo De Los Rios,Pierre Goloubinoff

{"title":"Hsp110 Nucleotide Exchange Factors may amplify Hsp70-disaggregation by enhanced entropic pulling.","authors":"Mathieu E Rebeaud,Bruno Fauvet,Paolo De Los Rios,Pierre Goloubinoff","doi":"10.1016/j.jbc.2025.110450","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110450","url":null,"abstract":"Hsp70s use energy from ATP hydrolysis to unfold protein structures and solubilize stable aggregates and accumulate native species, even under adverse non-native conditions. To carry out its catalytic polypeptide-unfolding activity, Hsp70 needs to reversibly interact with a J-domain (JDP) catalyst, a misfolded or alternatively-folded polypeptide substrate and a Nucleotide Exchange Factor (NEF), which binds to the Nucleotide Binding Domain (NBD), accelerates ADP-release and controls the dissociation of the unfolded polypeptide product of the unfolding reaction. In bacteria, GrpE is the ubiquitous NEF, and yet, during the process of eukaryotisation, it was lost from the cytosol, to be replaced by novel NEF proteins, among which the Hsp110 family stands out. Curiously, Hsp110s belong to the Hsp70 superfamily, but the evolutionary steps that led from an ancestral Hsp70 unfoldase to a Hsp110 NEF catalyzing other Hsp70's activity, remain unsolved. Combining experiments using wild-type Sse1 (yeast Hsp110) and rationally designed mutants, we show that Hsp110 is likely built upon some distinctive features already present in Hsp70 by repurposing them, rather than by fashioning novel molecular properties. Taking all results together, we suggest a novel mechanism of action of Hsp110, whereby it is a NEF that also enhances the unfolding/disaggregating entropic pulling forces generated by Hsp70, by transiently increasing the chaperone effective volume.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"76 1","pages":"110450"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polyamines stimulate the protein synthesis of the initiation factor eIF5A2 participating in mRNA decoding distinct from eIF5A1. 多胺刺激起始因子eIF5A2的蛋白质合成，参与mRNA解码，与eIF5A1不同。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110453

Masato Suzuki,Takehiro Suzuki,Yoshio Nakano,Ken Matsumoto,Hitomi Manaka,Masahiro Komeno,Shoma Tamori,Akira Sato,Naoshi Dohmae,Kazunori Akimoto,Satoru Miyazaki,Takashi Suda,Toshihiko Toida,Keiko Kashiwagi,Kazuei Igarashi,Kyohei Higashi

{"title":"Polyamines stimulate the protein synthesis of the initiation factor eIF5A2 participating in mRNA decoding distinct from eIF5A1.","authors":"Masato Suzuki,Takehiro Suzuki,Yoshio Nakano,Ken Matsumoto,Hitomi Manaka,Masahiro Komeno,Shoma Tamori,Akira Sato,Naoshi Dohmae,Kazunori Akimoto,Satoru Miyazaki,Takashi Suda,Toshihiko Toida,Keiko Kashiwagi,Kazuei Igarashi,Kyohei Higashi","doi":"10.1016/j.jbc.2025.110453","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110453","url":null,"abstract":"Polyamines are present in all living organisms, and their homeostasis is closely associated with human health and disease. Further, they are small aliphatic cations that exhibit multifunctional activities through interactions with acidic substances, thereby precluding our understanding of their molecular functions in biological processes. eIF5A1 and eIF5A2 share high amino acid sequence similarity, and hypusination, using spermidine, is essential for their functions. eIF5A1 is ubiquitously expressed in all tissues and is essential for normal cell growth, whereas eIF5A2 is often expressed in human cancer tissues; however, the functional differences between eIF5A1 and eIF5A2 remain unclear. Here, we found that eIF5A2 is regulated by polyamines at the translational level and that eIF5A2, rather than eIF5A1, is important for cancer cell growth. The translational initiation of eIF5A2 mRNA was negatively regulated by miR-6514-5p at the 5'-UTR, and polyamines inhibited this miRNA function, facilitating eIF5A2 synthesis. A proteomic analysis of cells with either eIF5A1 or eIF5A2 silenced showed distinct profiles. In addition, polyamines upregulated the expression of five ribosomal proteins, particularly RPS27A, RPL36A, and RPL22L1, which are associated with cancer malignancy. Our findings reveal an important role for eIF5A2, regulated by polyamines and miR-6514-5p, in cancer cell proliferation, suggesting that the interaction between eIF5A2 and ribosomes, which regulate cancer progression, is a selective target for cancer treatment.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"20 1","pages":"110453"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bioluminescence-based assays for quantifying endogenous protein interactions in live cells. 基于生物发光的测定活细胞内源性蛋白相互作用的方法。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110454

Andrew L Niles,Michael R C Dibble,Thomas Machleidt,Kelli Martino,Matthew R Swiatnicki,Elizabeth H Vu,Marie K Schwinn

{"title":"Bioluminescence-based assays for quantifying endogenous protein interactions in live cells.","authors":"Andrew L Niles,Michael R C Dibble,Thomas Machleidt,Kelli Martino,Matthew R Swiatnicki,Elizabeth H Vu,Marie K Schwinn","doi":"10.1016/j.jbc.2025.110454","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110454","url":null,"abstract":"Protein-protein interactions (PPIs) are integral to cellular signaling networks and are frequently disrupted in cancer, neurodegeneration, inflammation, and metabolic disorders. Targeting dysregulated PPI presents a promising strategy for development of therapeutic compounds. However, traditional drug discovery platforms often rely on plasmid-driven overexpression models that fail to replicate the complexity and dynamics of PPI in native cellular contexts. This study aims to evaluate the use of NanoLuc Binary Technology (NanoBiT) and NanoLuc Bioluminescence Resonance Energy Transfer (NanoBRET) for quantifying interactions of endogenously regulated proteins in live cells. To achieve this, CRISPR-mediated genome engineering was used to integrate NanoBiT and NanoBRET fusion tags at the loci for EGFR/GRB2 and KRas/CRAF in DLD-1 and HCT 116 cell lines. Assays using the engineered cell lines were then conducted in monolayer cultures using endpoint and kinetic measurements, as well as luminescence imaging. The approach was further expanded to investigate PPI in cancer-associated isogenic cell lines and 3D spheroid models that better preserve additional aspects of cellular organization. Collectively, these findings establish a robust and modular workflow for generating endogenously regulated PPI reporter cell lines to improve relevance and predictive power of live-cell assays. By capturing interaction dynamics in a more representative background, this approach offers a potentially valuable tool for elucidating signaling mechanisms and characterizing therapeutic compounds targeting PPIs.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"20 1","pages":"110454"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inflamed endothelial cells express S1PR1 inhibitor CD69 to induce vascular leak. 炎症内皮细胞表达S1PR1抑制剂CD69诱导血管渗漏。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110455

Michel V Levesque,Andreane Cartier,Yueh-Chien Lin,Raj Kumar Sah,Hanming Zhang,Balkhrisa Chaube,Mantu Bhaumik,Jakob Körbelin,Yajaira Suárez,Carlos Fernández-Hernando,Timothy Hla

{"title":"Inflamed endothelial cells express S1PR1 inhibitor CD69 to induce vascular leak.","authors":"Michel V Levesque,Andreane Cartier,Yueh-Chien Lin,Raj Kumar Sah,Hanming Zhang,Balkhrisa Chaube,Mantu Bhaumik,Jakob Körbelin,Yajaira Suárez,Carlos Fernández-Hernando,Timothy Hla","doi":"10.1016/j.jbc.2025.110455","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110455","url":null,"abstract":"Inflammation disrupts endothelial barrier function and causes vascular leak into the tissue parenchyma. Sphingosine 1-phosphate receptor-1 (S1PR1) in endothelial cells (EC) is a key inducer of endothelial junctions and barrier function. We report here that endothelial cell activation by the cytokine TNFα and TLR3 agonist poly-inosine/cytosine (pI:C) induces the lymphocyte activation molecule CD69 via the canonical NFκB pathway. EC CD69 stimulates endocytosis of S1PR1, inhibits its downstream intracellular signaling events and barrier function. Administration of TLR4 or TLR3 agonists or intranasal infection of mouse-adapted influenza virus (H1N1) or coronavirus (MHV-A59) induced CD69 in lung endothelial cells. AAV-mediated overexpression of CD69 in lung EC leads to decreased cell-surface expression of S1PR1 and tight junction protein Claudin-5, concomitantly with increased vascular permeability in the lungs. Further, lung vascular leak at the peak of H1N1 infection is attenuated in a genetic mouse model which lacks CD69 in the endothelium. These data suggest that endothelial activation during inflammation and viral host-defense induces CD69 which downregulates S1PR1 to induce vascular leakage. CD69 induction during endothelial dysfunction may drive exaggerated inflammation by antagonizing the endothelial protective S1PR1 pathway.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"27 1","pages":"110455"},"PeriodicalIF":4.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineered bacteriophytochrome heterodimers for research and applications. 工程细菌色素异二聚体的研究与应用。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-03 DOI: 10.1016/j.jbc.2025.110452

Iida Tuure,Cornelia Böhm,Jessica Rumfeldt,Elina Multamäki,Heikki Takala

引用次数: 0

Vacuole Protein Sorting 18 (Vps18) Suppresses Epithelial Growth Factor Receptor (EGFR) Expression and Tumorigenesis. 液泡蛋白分类18 （Vps18）抑制上皮生长因子受体（EGFR）表达和肿瘤发生。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-02 DOI: 10.1016/j.jbc.2025.110447

Wuhou Dai, Shujing Zhang, Shunfei Yan, Hao Zhang, Sha Zou, Tonglu Yu, Wufan Tao, Hengning Ke, Xingrong Du

引用次数: 0

Systematic characterization of zinc in a series of breast cancer cell lines reveals significant changes in zinc homeostasis. 锌在一系列乳腺癌细胞系中的系统表征揭示了锌稳态的显著变化。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-02 DOI: 10.1016/j.jbc.2025.110442

Mena Woyciehowsky, Portia Larson, Annika R Stephan, Sharee L Dandridge, Doreen Idonije, Kylie A Berg, Alyx Lanthier, Stephanie Araiza Acuna, Saskia W Stites, Waverly J Gebhardt, Samuel E Holtzen, Ananya Rakshit, Amy E Palmer

{"title":"Systematic characterization of zinc in a series of breast cancer cell lines reveals significant changes in zinc homeostasis.","authors":"Mena Woyciehowsky, Portia Larson, Annika R Stephan, Sharee L Dandridge, Doreen Idonije, Kylie A Berg, Alyx Lanthier, Stephanie Araiza Acuna, Saskia W Stites, Waverly J Gebhardt, Samuel E Holtzen, Ananya Rakshit, Amy E Palmer","doi":"10.1016/j.jbc.2025.110442","DOIUrl":"10.1016/j.jbc.2025.110442","url":null,"abstract":"An optimal amount of zinc (Zn2+) is essential for proliferation of human cells; Zn2+ levels that are too high or too low cause cell cycle exit. Tumors of the breast have been characterized by high levels of total Zn2+. Given the role of Zn2+ in proliferation of human cells and elevation of zinc in breast cancer tumors, we examined the concentration of total and labile Zn2+ across a panel of 5 breast cancer cell lines, compared to the normal MCF10A cell line. We found that three cell lines (MDA-MB-231, MDA-MB-157, and SK-Br-3) showed elevated labile Zn2+ in the cytosol, while T-47D showed significantly lower Zn2+, and MCF7 showed no change compared to MCF10A cells. There was no change in total Zn2+ across the cell lines, as measured by ICP-MS, but we did observe a difference in the cells ability to accumulate Zn2+ when Zn2+ in the media was elevated. Therefore, we examined how proliferation of each cell line was affected by increases and decreases in the media. We found striking differences, where three cancer cell lines (MDA-MB-231, MDA-MB-157, and MCF7) showed robust proliferation in high Zn2+ at concentrations that killed MCF10A, T-47D, and SK-Br-3 cells. We also discovered that 4 of the 5 cancer cell lines demonstrate compromised proliferation and increased cell death in low Zn2+, suggesting these cells may be addicted to Zn2+. Overall, our study suggests significant differences in Zn2+ homeostasis and regulation in different types of breast cancer cells, with consequences for both proliferation and cell viability.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110442"},"PeriodicalIF":4.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GoLoco/GPR Motif-Dependent Regulation of Rap1GAP1 by Gα_o is Disrupted by Gα_o Encephalopathy Variants. GoLoco/GPR基序依赖的Gαo对Rap1GAP1的调控被Gαo脑病变体破坏。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-07-02 DOI: 10.1016/j.jbc.2025.110446

Nathalie L Momplaisir, Naincy R Chandan, Beiyun Wang, Elaine Qu, Alan V Smrcka

{"title":"GoLoco/GPR Motif-Dependent Regulation of Rap1GAP1 by Gαo is Disrupted by Gαo Encephalopathy Variants.","authors":"Nathalie L Momplaisir, Naincy R Chandan, Beiyun Wang, Elaine Qu, Alan V Smrcka","doi":"10.1016/j.jbc.2025.110446","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110446","url":null,"abstract":"G protein-coupled receptors (GPCRs) that couple to Gαi/o family members are major therapeutic targets. Among heterotrimeric G proteins, Gαo is the most abundant Gα subunit in the brain but the mechanistic pathways controlled by Gαo have not been thoroughly established. Understanding Gαo-mediated signalling pathways is especially critical given recent reports of a neurodevelopmental disorder (GNAO1 encephalopathy) associated with mutations in the Gαo-encoding gene. To address this gap, we sought to uncover novel Gαo effectors using a proximity-based proteomics screen in differentiated PC12 cells. Our analysis revealed a diverse set of potential Gαo-GTP effector proteins including a Rap1 GTPase activating protein, Rap1GAP1. Regulation of Rap1GAP1 by G protein α subunits is controversial, with Rap1GAP1 reported to bind preferentially to Gαo-GDP via a GoLoco/G protein regulatory (GPR) motif. We establish that Gαo-GTP binds and regulates Rap1GAP1 activity and reveal a novel mechanism for Gα subunit recognition by Rap1GAP1 where the presence or absence of key contact residues in the GoLoco/GPR motif confer differential recognition of Gαo guanine nucleotide binding status. We also show that pathologic GNAO1 mutations disrupt this functional relationship by preventing the activated Gα subunit from attaining a conformation required for effector binding. These data resolve controversies in the literature regarding activation-dependent binding and regulation of Rap1GAP by Gαo and help establish Rap1GAP1a as a bone fide G protein regulated effector. Furthermore, our study finds that multiple mutants in Gαo associated with GNAO1 encephalopathy have defects in downstream effector interactions, which could underly some of the manifestations of this disease.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110446"},"PeriodicalIF":4.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0