Biochimica et biophysica acta. Proteins and proteomics最新文献_第7页

Computing pathogenicity of mutations in human cytochrome P450 superfamily 计算人类细胞色素P450超家族突变的致病性

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-07-01 Epub Date: 2025-05-09 DOI: 10.1016/j.bbapap.2025.141078

Somnath Mondal , Pranchal Shrivastava , Rukmankesh Mehra

{"title":"Computing pathogenicity of mutations in human cytochrome P450 superfamily","authors":"Somnath Mondal , Pranchal Shrivastava , Rukmankesh Mehra","doi":"10.1016/j.bbapap.2025.141078","DOIUrl":"10.1016/j.bbapap.2025.141078","url":null,"abstract":"<div><div>Cytochrome P450 (CYPs) are crucial heme-containing enzymes that metabolize drugs and endogenous compounds. In humans, 57 CYP isoforms have been identified, with over 200 mutations linked to severe disorders. Our comprehensive computational study assessed the reason for the pathogenicity of mutations by comparing pathogenic and non-pathogenic variants. We analyzed 25,94,151 mutations across 26 CYP structures using structure- and sequence-based methods, revealing a meaningful stability pattern: non-pathogenic > all > pathogenic mutation datasets. Notably, pathogenic mutations were predominantly buried within CYP structures, indicating a higher potential for pathogenesis. We identified three key amino acid properties affected by mutations: Gibbs free energy, isoelectric point, and volume. Furthermore, diseased mutations significantly reduced positive residue content, particularly due to arginine mutations, which directly influenced the isoelectric point. Our findings indicate a greater likelihood of pathogenic mutations occurring at conserved sites, disrupting CYP function. A higher frequency of pathogenic mutations was observed in heme sites, primarily involving arginine, which may interfere with arginine-heme interactions. Molecular docking revealed a differential binding of heme in wild-type and pathogenic CYPs. This study provides a foundational analysis of mutation effects across multiple CYPs. It models the chemical basis of CYP-related pathogenicity, facilitating the development of a semi-quantitative disease prediction model.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141078"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synovial fluid glycoproteome profiling in knee osteoarthritis: Molecular insights into type 2 diabetes-associated biomarkers and therapeutic targets 膝关节骨关节炎的滑液糖蛋白组分析：2型糖尿病相关生物标志物和治疗靶点的分子见解

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-07-01 Epub Date: 2025-03-27 DOI: 10.1016/j.bbapap.2025.141067

Monidipa Konar , Bhavneet Kaur , Uttam Chand Saini , Sanjay K. Bhadada , Sadhna Sharma

{"title":"Synovial fluid glycoproteome profiling in knee osteoarthritis: Molecular insights into type 2 diabetes-associated biomarkers and therapeutic targets","authors":"Monidipa Konar , Bhavneet Kaur , Uttam Chand Saini , Sanjay K. Bhadada , Sadhna Sharma","doi":"10.1016/j.bbapap.2025.141067","DOIUrl":"10.1016/j.bbapap.2025.141067","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) and Osteoarthritis (OA) share common risk factors like age, obesity and hypertension. Currently, 52 % of diabetic patients suffer from arthritis. Diabetes facilitates OA by altering lipid metabolism, levels of adipokines & cytokines, accumulation of advanced glycation end products, etc., which affects cartilage & bone health. However, the molecular mechanisms of the association of OA with T2DM remain unexplored. Since diabetes greatly affects the glycosylation status of proteins, the present study focused on identifying glycoproteins that could serve as diagnostic and prognostic markers for identifying osteoarthritis in diabetic individuals by LC-MS/MS. Comparative proteomic analysis revealed 20 significantly altered glycoproteins; among them, thyroxine-binding globulin (THBG), alpha-1-antitrypsin (A1AT), fibrinogen gamma chain (FGG) and angiotensinogen (AGT) were further validated. THBG, A1AT and AGT showed promising potential to identify the comorbid condition in serum and synovial fluid, however, ROC analysis identified THBG as the best candidate glycoprotein marker. Upregulation of THBG in OADM disrupts the bone remodeling cycle, degrades insulin, and promotes the expression of GLUT-1 and MMP-9. Overall, THBG could also serve as a therapeutic target for reducing the progression of osteoarthritis and alleviating pain and bone stiffness associated with the disease.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141067"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

TMB Stab-pred: Predicting the stability of transmembrane β-barrel proteins using their sequence and structural signatures TMB Stab-pred：利用β-桶跨膜蛋白的序列和结构特征预测其稳定性。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-07-01 Epub Date: 2025-04-04 DOI: 10.1016/j.bbapap.2025.141070

P. Ramakrishna Reddy, A. Kulandaisamy, M. Michael Gromiha

{"title":"TMB Stab-pred: Predicting the stability of transmembrane β-barrel proteins using their sequence and structural signatures","authors":"P. Ramakrishna Reddy, A. Kulandaisamy, M. Michael Gromiha","doi":"10.1016/j.bbapap.2025.141070","DOIUrl":"10.1016/j.bbapap.2025.141070","url":null,"abstract":"<div><div>Understanding the folding and stability of transmembrane β-barrel proteins (TMBs) provides insights into their structural integrity, functional mechanisms, and implications for disease states. In this work, we have characterized the important features that influence the folding and stability of TMBs. Our results showed that lipid accessible surface area and transition energy are important for understanding the stability of TMBs. Further, this information was utilized to develop a linear regression-based method for predicting the stability of TMBs. Our method achieved a correlation and mean absolute error (MAE) of 0.96 and 0.94 kcal/mol on the jack-knife test. Moreover, we compared the stability of TMBs with globular all-β proteins and observed that long-range interactions and energetic properties are crucial for maintaining the stability of both β-barrel membrane and all-β globular proteins. On the other hand, side-chain – side-chain hydrogen bonds and lipid accessible surface area are specific to membrane proteins. These features are critical for membrane proteins because they influence a protein to embed within the membrane environment. Further, we have developed a web server, TMB Stab-pred for predicting the stability of TMBs, and it is accessible at <span><span>https://web.iitm.ac.in/bioinfo2/TMBB/index.html</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141070"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Evolution of Chlorella sp. RCC288 proteome and transcriptome during its adaptation to oil mill wastewater 小球藻RCC288对油厂废水适应过程中蛋白质组和转录组的进化

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-07-01 Epub Date: 2025-05-05 DOI: 10.1016/j.bbapap.2025.141077

Bouthaina Menaa , Rihab Hachicha , Pascal Dubessay , Slim Abdelkafi , Imen Fendri , Philippe Michaud

{"title":"Evolution of Chlorella sp. RCC288 proteome and transcriptome during its adaptation to oil mill wastewater","authors":"Bouthaina Menaa , Rihab Hachicha , Pascal Dubessay , Slim Abdelkafi , Imen Fendri , Philippe Michaud","doi":"10.1016/j.bbapap.2025.141077","DOIUrl":"10.1016/j.bbapap.2025.141077","url":null,"abstract":"<div><div>Some species of microalgae, including <em>Chlorella</em>, can utilize a variety of dissolved organic carbon sources, such as sugars and organic acids, for growth. In the presence of both light and these organic substrates, they exhibit mixotrophic metabolism, combining heterotrophic assimilation of organic carbon with photosynthetic carbon fixation. In this study, we analyzed using proteomic and transcriptomic approaches the ability of <em>Chlorella</em> sp. to shift its metabolism when it was grown in photoautotrophy in BG-11 medium and mixotrophy in 30 % diluted olive mill wastewaters (OMWWs) pretreated with laccases. Using UniProt, InterPro, KEGG Pathway, and Gene Ontology databasesproteomic and transcriptomic data have been analyzed. In mixotrophy, over-expression of cell cycle, signaling, and transport proteins, as well as chaperone proteins, were identified and associated with an overall decrease in photosynthesis and carbohydrate/lipid metabolic pathways. In addition, the expression of light-independent protochlorophyllide reductase, malate synthase, acetyl-CoA carboxylase and pyruvate kinase were modulated. Surprisingly an upregulation of the ammonium transporter protein, which could play a role in OMWWs detoxification was detected. Homology modeling investigation of the three-dimensional structure of ammonium transporter protein revealed that it holds a functional trimeric structure with a lengthy C-terminal region that may be involved in the regulation and activation of ammonium transport.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141077"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Biophysical analysis of SECIS binding protein 2 (SBP2) from Naegleria gruberi 格氏耐格氏菌SECIS结合蛋白2 （SBP2）的生物物理分析

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-07-01 Epub Date: 2025-04-26 DOI: 10.1016/j.bbapap.2025.141075

Jéssica Fernandes Scortecci , Adriano de Freitas Fernandes , Vitor Hugo Balasco Serrão , Marinônio Lopes Cornélio , Mario de Oliveira Neto , Otavio Henrique Thiemann

{"title":"Biophysical analysis of SECIS binding protein 2 (SBP2) from Naegleria gruberi","authors":"Jéssica Fernandes Scortecci , Adriano de Freitas Fernandes , Vitor Hugo Balasco Serrão , Marinônio Lopes Cornélio , Mario de Oliveira Neto , Otavio Henrique Thiemann","doi":"10.1016/j.bbapap.2025.141075","DOIUrl":"10.1016/j.bbapap.2025.141075","url":null,"abstract":"<div><div>The Selenocysteine (Sec - U) biosynthesis pathway is present in eukaryotes and prokaryotes, in which its incorporation is directed by the stop codon UGA and the structural mRNA element named Sec Insertion Sequence (SECIS) that contain an essential kink-turn motif recognized by specific RNA-binding proteins. SBP2 is the key player in the interaction with the SECIS element in eukaryotes, and it is essential for the biosynthesis pathway. Free-living amoebas are part of the Heterolobosea phylum, and several species, including <em>Naegleria fowleri</em>, are known human pathogens. In 2013 it was reported that <em>Naegleria gruberi</em> (<em>Ng</em>SBP2), which is non-pathogenic, had a divergent SBP2 sequence and all the genes essential for Sec synthesis. The identity of <em>Ng</em>SBP2 is confirmed experimentally and its binding affinity to the SECIS element is demonstrated. The N-terminal and the C-terminal domains (<em>Ng</em>SBP2-NT and <em>Ng</em>SBP2-CT, respectively) of <em>Ng</em>SBP2 contain disordered regions, particularly in the N-terminal domain. The SECIS element is bonded to NgSBP2-CT, which results in a decrease in the disordered sequence of the domain, and the NgSBP2-NT domain interacts with NgSBP2-CT.SECIS complex, as we present here. The findings reveal the molecular interaction patterns underlying the selenocysteine incorporation pathway in an early-branching eukaryote, which is influenced by multiple protein-RNA interactions.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 4","pages":"Article 141075"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Participation of a cysteine tetrad in the recycling mechanism of methionine sulfoxide reductase A from radiation-tolerant Deinococcus bacteria 半胱氨酸四分体参与耐辐射球菌甲硫氨酸亚砜还原酶a的循环机制。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-05-01 Epub Date: 2025-02-08 DOI: 10.1016/j.bbapap.2025.141063

Pascal Rey , Nicolas Rouhier , Chloé Carassus , Arjan de Groot , Laurence Blanchard

{"title":"Participation of a cysteine tetrad in the recycling mechanism of methionine sulfoxide reductase A from radiation-tolerant Deinococcus bacteria","authors":"Pascal Rey , Nicolas Rouhier , Chloé Carassus , Arjan de Groot , Laurence Blanchard","doi":"10.1016/j.bbapap.2025.141063","DOIUrl":"10.1016/j.bbapap.2025.141063","url":null,"abstract":"<div><div>Methionine oxidation leads to the formation of methionine sulfoxide (MetO), which is reduced back to Met by methionine sulfoxide reductases (Msrs). The catalytic mechanism used by A-type Msr (MsrA) for MetO reduction requires a catalytic cysteine (Cys), which is converted to a sulfenic acid. In general, two resolving Cys are required for the regeneration of the catalytic Cys forming two consecutive disulfide bridges, the last one being efficiently reduced by thioredoxin (Trx). Here, we performed the biochemical characterization of MsrA from <em>Deinococcus deserti</em>. It possesses four Cys, two present in the active site motif (18 and 21) and two distal ones (53 and 163). We produced MsrA variants mutated for these cysteines and analyzed their capacity to reduce MetO in the presence of the NADPH-Trx reductase/Trx system, their ability to form heterodimers with Trxs, and their redox status after incubation with MetO. We show that all four Cys are involved in the regeneration process of enzyme activity by Trx. After MetO reduction by Cys18, a first disulfide bridge is formed with Cys21. A second disulfide involving Cys21 with either Cys53 or Cys163 is reduced by Trx, and a third Cys53-Cys163 disulfide can be formed and also reduced by Trx. These findings highlighting for the first time the involvement of a Cys tetrad in the catalytic and regeneration mechanisms for a MsrA are placed in a structural context by performing 3D modelling and discussed in relation to the known recycling mechanisms involving a Cys triad.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 3","pages":"Article 141063"},"PeriodicalIF":2.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DSP-1, the major fibronectin type-II protein of donkey seminal plasma is a small heat-shock protein and exhibits chaperone-like activity against thermal and oxidative stress DSP-1是驴精浆中主要的ii型纤维连接蛋白，是一种小的热休克蛋白，对热应激和氧化应激具有类似伴侣蛋白的活性。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-05-01 Epub Date: 2025-02-15 DOI: 10.1016/j.bbapap.2025.141064

Sk Alim , Sudheer K. Cheppali , Sonali S. Pawar, Musti J. Swamy

{"title":"DSP-1, the major fibronectin type-II protein of donkey seminal plasma is a small heat-shock protein and exhibits chaperone-like activity against thermal and oxidative stress","authors":"Sk Alim , Sudheer K. Cheppali , Sonali S. Pawar, Musti J. Swamy","doi":"10.1016/j.bbapap.2025.141064","DOIUrl":"10.1016/j.bbapap.2025.141064","url":null,"abstract":"<div><div>Fibronectin type-II (FnII) proteins are major constituents in the seminal plasma of many mammals and play a crucial role in sperm capacitation. Additionally, the seminal FnII proteins from bull and horse exhibit chaperone-like activity (CLA), by acting as small heat shock proteins (<em>shsp</em>s). The present work demonstrates that the major FnII protein of donkey seminal plasma, DSP-1 exhibits CLA with broad specificity and protects various client proteins such as alcohol dehydrogenase, lactate dehydrogenase and enolase against thermal and oxidative stress. Binding of phosphorylcholine (PrC) – the head group moiety of choline phospholipids, which are the physiological ligands of DSP-1 – decreased the CLA whereas binding of 1,2-dioleoyl-<em>sn</em>-glycero-3-phospholcholine (DOPC) increased the CLA. Biophysical studies suggested that these contrasting effects on the CLA by phosphorylcholine and diacyl phosphatidylcholine could be attributed to changes in the surface hydrophobicity of DSP-1 upon binding to these ligands. Interestingly, binding of PrC reduced DSP-1 tetramers to monomers with lower surface hydrophobicity, whereas binding to DOPC liposomes increased its surface hydrophobicity. These results, which demonstrate that DSP-1 exhibits CLA and functions as a molecular chaperone, expand the family of mammalian seminal FnII proteins that function as <em>shsp</em>s.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 3","pages":"Article 141064"},"PeriodicalIF":2.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Tracking heme biology with resonance Raman spectroscopy 用共振拉曼光谱跟踪血红素生物学。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-05-01 Epub Date: 2025-02-23 DOI: 10.1016/j.bbapap.2025.141065

Amanda Bartkowiak, Ewa Szczesny-Malysiak, Jakub Dybas

{"title":"Tracking heme biology with resonance Raman spectroscopy","authors":"Amanda Bartkowiak, Ewa Szczesny-Malysiak, Jakub Dybas","doi":"10.1016/j.bbapap.2025.141065","DOIUrl":"10.1016/j.bbapap.2025.141065","url":null,"abstract":"<div><div>Heme proteins are a large group of biomolecules with heme incorporated as a prosthetic group. Apart from cytochromes present in almost all cell types, many other specific heme proteins are expressed in different kinds of cells, e.g. hemoglobin in the erythrocytes, myoglobin (skeletal and vascular smooth muscle cells), cytoglobin (fibroblasts) and neuroglobin (neurons and retina). Among their wide and diverse biological functions, the most important is their unique ability to bind, store, and transport gaseous molecules, such as oxygen, carbon monoxide, and nitric oxide. Resonance Raman (RR) spectroscopy is an exceptional analytical tool that allows for qualitative and quantitative characterization of heme proteins in biological systems. Due to its high sensitivity, even subtle structural alterations of the heme group can be monitored and tracked during cellular processes. Resonance Raman excitation within the Soret absorption band (390–440 nm) provides rich information on the environment of heme's active site, allowing differentiation of the iron ion oxidation and spin states, and tracking the movement of the porphyrin ring plane in response to the changes in oxygenation status. Herein, we summarize and discuss recent developments in RR applications aimed to link the structure-function relationship of heme proteins within biological systems, connected, e.g., with the formation of hemoglobin (Hb) adducts (nitrosylhemoglobin, cyanhemoglobin, sulfhemoglobin), irreversible Hb alterations deteriorating oxygen binding and differentiation of heme proteins oxidation state within live cells in situ.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 3","pages":"Article 141065"},"PeriodicalIF":2.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Elucidation of cytotoxicity of α-Synuclein fibrils on immune cells α-突触核蛋白原纤维对免疫细胞的细胞毒性研究。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-02-01 Epub Date: 2024-12-16 DOI: 10.1016/j.bbapap.2024.141061

Mikhail Matveyenka , Abid Ali , Charles L. Mitchell , Mikhail Sholukh , Dmitry Kurouski

{"title":"Elucidation of cytotoxicity of α-Synuclein fibrils on immune cells","authors":"Mikhail Matveyenka , Abid Ali , Charles L. Mitchell , Mikhail Sholukh , Dmitry Kurouski","doi":"10.1016/j.bbapap.2024.141061","DOIUrl":"10.1016/j.bbapap.2024.141061","url":null,"abstract":"<div><div>Progressive aggregation of α-synuclein (α-Syn), a small cytosolic protein involved in cell vesicle trafficking, in the midbrain, hypothalamus, and thalamus is linked to Parkinson's disease (PD). Amyloid oligomers and fibrils formed as a result of such aggregation are highly toxic to neurons. However, it remains unclear whether amyloid-induced toxicity of neurons is the primary mechanism of the progressive neurodegeneration observed upon PD. In the current study, we investigated cytotoxicity exerted by α-Syn fibrils formed in the lipid-free environment, as well as in the presence of two phospholipids, on macrophages, dendritic cells, and microglia. We found that α-Syn fibrils are far more toxic to dendritic cells and microglia compared to neurons. We also observe low toxicity levels of such amyloids to macrophages. Real-time polymerase chain reaction (RT-PCR) results suggest that toxicity of amyloids aggregates is linked to the levels of autophagy in cells. These results suggest that a strong impairment of the immune system in the brain may be the first stop of neurodegenerative processes that are taking place upon the onset of PD.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 2","pages":"Article 141061"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Replacement of the essential catalytic aspartate with serine leads to an active form of copper-containing nitrite reductase from the denitrifier Sinorhizobium meliloti 2011 用丝氨酸取代必需的催化天门冬氨酸导致反硝化菌Sinorhizobium meliloti 2011中含铜亚硝酸盐还原酶的活性形式。

IF 2.5 4区生物学

Biochimica et biophysica acta. Proteins and proteomics Pub Date : 2025-02-01 Epub Date: 2024-12-30 DOI: 10.1016/j.bbapap.2024.141062

Lorieth A. Guevara Cuasapud , Pablo J. González , Félix M. Ferroni , Andrea B. Duré , Sergio D. Dalosto , Maria G. Rivas , Carlos D. Brondino

{"title":"Replacement of the essential catalytic aspartate with serine leads to an active form of copper-containing nitrite reductase from the denitrifier Sinorhizobium meliloti 2011","authors":"Lorieth A. Guevara Cuasapud , Pablo J. González , Félix M. Ferroni , Andrea B. Duré , Sergio D. Dalosto , Maria G. Rivas , Carlos D. Brondino","doi":"10.1016/j.bbapap.2024.141062","DOIUrl":"10.1016/j.bbapap.2024.141062","url":null,"abstract":"<div><div>We report the molecular, biochemical and spectroscopic characterization and computational calculations of a variant of the copper-containing nitrite reductase from the rhizobial microorganism <em>S. meliloti</em> (<em>Sm</em>NirK), in which the catalytic aspartate residue (Asp<sub>CAT</sub>) has been replaced with serine (Ser<sub>CAT</sub>, D134S) by site-directed mutagenesis. Like the wild-type enzyme, D134S is a homotrimer with the typical catalytic pocket of two-domain NirK containing two copper centers, one of type 1 (T1) and another of type 2 (T2). The T1 electron transfer center is similar to that of the wild-type enzyme but the electronic and covalent properties of T2 active site are altered by the mutation. As for the wild-type enzyme, the enzymatic activity of D134S is pH-dependent, i.e. it is higher at lower pH values, but the <em>k</em><sub>cat</sub> is an order of magnitude lower. EPR studies showed a decrease in <em>g</em><sub>‖</sub> and an increase in <em>A</em><sub>‖</sub> of D134S relative to wild-type enzyme. This indicates changes in the electronic and covalent properties of T2 upon mutation, which affects the reduction potential of T2 and the T1-T2 reduction potential gap. Taken together, this evidence points to the importance of the ligands of the second coordination sphere of T2 in controlling critical parameters in catalysis. The possibility that Asp<sub>CAT</sub>/Ser<sub>CAT</sub> is the switch that triggers T1 → T2 electron transfer upon T2 nitrite binding and the importance of His<sub>CAT</sub> for the pH-dependent catalytic activity of NirK are discussed.</div></div>","PeriodicalId":8760,"journal":{"name":"Biochimica et biophysica acta. Proteins and proteomics","volume":"1873 2","pages":"Article 141062"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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