Biochemistry (Moscow)最新文献

{"title":"Peripheral Immune-Inflammatory Parameters in Parkinson’s Disease. Dependence on the Stage of Progression","authors":"Galina V. Idova,&nbsp;Svetlana Ya. Zhanaeva,&nbsp;Elizaveta L. Alperina,&nbsp;Sergei S. Dzemidovich,&nbsp;Margarita M. Gevorgyan,&nbsp;Kseniya I. Kulikova,&nbsp;Lyubomir I. Aftanas","doi":"10.1134/S0006297925600334","DOIUrl":"10.1134/S0006297925600334","url":null,"abstract":"<p>According to the modern concepts, neuroinflammation and peripheral immune dysfunction play key roles in the onset and progression of Parkinson’s disease (PD), one of the most common and severe neurodegenerative diseases. However, changes in the cellular and molecular immune parameters during the development of PD are still poorly understood. This work is devoted to analysis of the immune cell populations (monocytes, T- and B-cells and their subtypes), expression of Toll-like receptors (TLR), and spontaneous and mitogen-induced production of pro- and anti-inflammatory cytokines in the peripheral blood of the patients at different stages of idiopathic PD and healthy individuals. It was shown that the stage II of PD is characterized by the decrease in amount of the CD3⁺ T-cells, increase in the TLR2 expression on CD4⁺CD25⁺ Tregs, as well as increase in the spontaneous production of proinflammatory cytokines IFNγ and IL-17A. The stage III of PD is associated with the decrease in production of mitogen-induced IFNγ. Relative number of the CD19⁺CD25⁺ Breg cells in the patients with PD increased regardless of the disease stage. Thus, the obtained results indicate differences in the cellular and molecular immune parameters in the patients with PD and in the healthy individuals, which are dependent on the stage of the disease. These data are important for understanding molecular basis of PD development and prognosis of its course, and may be useful in identifying biomarkers of the disease severity and developing new treatment approaches depending on the stage of the disease.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"364 - 373"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919186","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}

{"title":"Development of Immunochemical Systems for Detection of Human Skeletal Troponin I Isoforms","authors":"Agnessa P. Bogomolova,&nbsp;Ivan A. Katrukha,&nbsp;Alexey M. Emelin,&nbsp;Artur I. Zabolotsky,&nbsp;Anastasia V. Bereznikova,&nbsp;Olga S. Lebedeva,&nbsp;Roman V. Deev,&nbsp;Alexey G. Katrukha","doi":"10.1134/S0006297924601928","DOIUrl":"10.1134/S0006297924601928","url":null,"abstract":"<p>Troponin I (TnI), together with troponin T (TnT) and troponin C (TnC), forms the troponin complex, a thin filament protein of the striated muscle that plays a key role in regulation of muscle contraction. In humans, TnI is represented by three isoforms: cardiac, which is synthesized only in myocardium, and fast and slow skeletal, which are synthesized in fast- and slow-twitch muscle fibers, respectively. Skeletal TnI isoforms could be used as biomarkers of skeletal muscle damage of various etiologies, including mechanical trauma, myopathies, muscle atrophy (sarcopenia), and rhabdomyolysis. Unlike classical markers of muscle damage, such as creatine kinase or myoglobin, which are also present in other tissues, skeletal TnIs are specific for skeletal muscle. In this study, we developed a panel of monoclonal antibodies for immunochemical detection of skeletal TnI isoforms using Western blotting (sensitivity: 0.01-1 ng per lane), immunohistochemical assays, and fluorescence immunoassays. Some of the designed fluorescence immunoassays enable quantification of fast skeletal (limit of detection [LOD] = 0.07 ng/mL) and slow skeletal (LOD = 0.1 ng/mL) TnI isoforms or both isoforms (LOD = 0.1 ng/ml). Others allow differential detection of binary (with TnC) or ternary (with TnT and TnC) complexes, revealing composition of troponin forms in the human blood.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"349 - 363"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S0006297924601928.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919214","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}

{"title":"Combined Ionizing Radiation Exposure Improves Behavioral Symptoms and Modulates Brain Innate Immune System Activity in the Tau P301S Mice Line","authors":"Viktor S. Kokhan,&nbsp;Ruslan A. Ageldinov,&nbsp;Petr K. Anokhin,&nbsp;Inna Yu. Shamakina","doi":"10.1134/S0006297924604453","DOIUrl":"10.1134/S0006297924604453","url":null,"abstract":"<p>Tauopathy is a group of neurodegenerative diseases associated with abnormal phosphorylation and aggregation of microtubule-associated tau protein. There are currently no disease-modifying therapies for the treatment of tauopathies, however, substantial evidence has shown that there is a major role of neuroinflammation in the disease progression. According to the literature, ionizing radiation (IR) may serve as an effective tool for managing neuroinflammation. In this study, we investigated effects of the combined IR (γ-rays and carbon-12 nuclei) on locomotor abilities and microglial activation markers in the brain of Tau P301S mice, a transgenic model for tauopathy. Irradiation resulted in the improvement of behavioral symptoms in mice: increased endurance and locomotor activity in the early symptomatic and terminal stages of the disease, respectively. At the same time, irradiation led to increase in the levels of both pro-inflammatory and anti-inflammatory cytokines in the cerebellum and, to a lesser extent, in the hippocampus of the irradiated animals. The obtained data indicate a significant modulatory effect of IR on the innate immune system, highlighting high potential of radiotherapy as a new strategy for neurodegenerative disease treatment.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"400 - 412"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919183","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}

{"title":"The Issue on Dualistic Role of Neutrophils in Carcinogenesis and Their Possible Use for Treatment of Malignant Neoplasms","authors":"Anna N. Gabashvili,&nbsp;Anastasiia A. Vasiukova,&nbsp;Aleksandra S. Rakitina,&nbsp;Anastasiia S. Garanina","doi":"10.1134/S000629792460368X","DOIUrl":"10.1134/S000629792460368X","url":null,"abstract":"<p>Neutrophils are phagocytic leukocytes of the myeloid series, which are the most common myeloid cells in human blood, normally accounting from 65 to 80% of all circulating leukocytes. Over the years of investigation of these cells, more and more evidence has emerged indicating functional plasticity of neutrophils and their ambiguous role in the tumor development. Similarly to the M1/M2 classification of macrophages, the N1/N2 paradigm could be applied to neutrophils, where N1-neutrophils exhibit tumor-suppressive properties, and N2-neutrophils contribute to tumor development and immune suppression. An important natural feature of neutrophils is their mobility and ability to overcome physical barriers, thus these cells, as well as their vesicles and membranes, could be used to deliver therapeutic drugs to tumor cells. In addition, neutrophils themselves could be activated and mobilized to fight the tumor. This review describes current state of research on the role of neutrophils in carcinogenesis, as well as possible approaches of using these cells and their derivatives as systems for targeted delivery of therapeutic drugs for treatment of malignant neoplasms.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"303 - 320"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919260","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}

{"title":"Mavacamten Inhibits the Effect of the N-Terminal Fragment of Cardiac Myosin-Binding Protein C with the L352P Mutation on the Actin–Myosin Interaction at Low Calcium Concentrations","authors":"Anastasia M. Kochurova,&nbsp;Evgenia A. Beldiia,&nbsp;Julia Y. Antonets,&nbsp;Victoria V. Nefedova,&nbsp;Natalia S. Ryabkova,&nbsp;Ivan A. Katrukha,&nbsp;Sergey Y. Bershitsky,&nbsp;Alexander M. Matyushenko,&nbsp;Galina V. Kopylova,&nbsp;Daniil V. Shchepkin","doi":"10.1134/S0006297924604131","DOIUrl":"10.1134/S0006297924604131","url":null,"abstract":"<p>Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin–myosin interaction and its calcium regulation and cause myocardial hypercontractility. About half of such mutations are found in the <i>MYBPC3</i> gene encoding cardiac myosin-binding protein C (cMyBP-C). A new approach to normalize cardiac contractile function in HCM is the use of β-cardiac myosin function inhibitors, one of which is mavacamten. We studied the effect of mavacamten on the calcium regulation of the actin–myosin interaction using isolated cardiac contractile proteins in the <i>in vitro</i> motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in the <i>in vitro</i> motility assay and the calcium sensitivity of the velocity but led to the underinhibition of the actin–myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments in the presence of the WT and L352P C0-C2 fragments, and abolished their movement in the presence of the L352P C0-C2 fragment at low calcium concentrations. Slowing down the kinetics of cross-bridges and inhibition of actin–myosin interaction at low calcium concentrations by mavacamten may reduce the hypercontractility in HCM and the degree of myocardial hypertrophy.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"389 - 399"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919184","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}

{"title":"Activation of Bacterial F-ATPase by LDAO: Deciphering the Molecular Mechanism","authors":"Sofya M. Bruman,&nbsp;Valeria M. Zubareva,&nbsp;Tatiana E. Shugaeva,&nbsp;Anna S. Lapashina,&nbsp;Boris A. Feniouk","doi":"10.1134/S0006297924602600","DOIUrl":"10.1134/S0006297924602600","url":null,"abstract":"<p>Proton F_OF₁ ATP synthase catalyzes the formation of ATP from ADP and inorganic phosphate coupled with transmembrane proton transfer using the energy of the protonmotive force (<i>pmf</i>). As <i>pmf</i> decreases, the direction of the reaction is reversed and the enzyme generates <i>pmf</i>, transferring protons across the membrane using the energy of ATP hydrolysis. ATPase activity of the enzyme can be suppressed by ADP in a non-competitive manner (ADP-inhibition), and in a number of bacteria, it can be inhibited by conformational changes in the regulatory C-terminal domain of the ε subunit. Lauryldimethylamine oxide (LDAO), a zwitterionic detergent, is known to attenuate both of these inhibitory mechanisms, significantly increasing the ATPase activity of the enzyme. For this reason, LDAO is sometimes used for semi-quantitative estimation of the enzyme’s susceptibility to these regulatory mechanisms. However, the binding site of LDAO in ATP synthase remains unknown. The mechanism by which the detergent counteracts ADP-inhibition and the inhibition involving the ε subunit is also unclear. We performed molecular docking and predicted that LDAO binding might occur at the catalytic site of ATP synthase, whether empty or containing nucleotides. Molecular dynamics simulations showed that LDAO could affect the mobility of the loop in the β subunit (residues β404-415 in <i>Escherichia coli</i> ATP synthase) near the catalytic site. Mutagenesis of residue β409 in the <i>E. coli</i> enzyme and the corresponding β419 residue in the <i>Bacillus subtilis</i> ATP synthase revealed that the type of side chain of this residue indeed affects LDAO-dependent stimulation of ATPase activity. We also found that LDAO activates the enzyme more strongly in the presence of 100 mM sulfate compared to sulfate-free medium. This phenomenon is likely due to the enhancement of ADP-inhibition of the enzyme by sulfate.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"374 - 388"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919187","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}

{"title":"Endocytosis Properties of GD2-Specific Antibodies in Tumor Cells","authors":"Alina O. Makarova,&nbsp;Matvey M. Titov,&nbsp;Daniel V. Kalinovsky,&nbsp;Irina V. Kholodenko,&nbsp;Alexey V. Kibardin,&nbsp;Sergey S. Larin,&nbsp;Elena V. Svirshchevskaya,&nbsp;Sergey M. Deyev,&nbsp;Roman V. Kholodenko","doi":"10.1134/S0006297925600395","DOIUrl":"10.1134/S0006297925600395","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) represent one of the most promising classes of monoclonal antibody-based (mAb) targeted cancer therapies. To date, 15 drugs of this class have received clinical approval, with numerous others under investigation in more than 100 clinical trials. Similarly to unconjugated antibodies, ADCs target various tumor markers including carbohydrate antigens such as glycosphingolipids. Among these targets, ganglioside GD2 is considered the most promising marker. Recent studies have demonstrated significant potential for the anti-GD2 ADCs in clinical application. Internalization of the antigen-antibody complexes and their subsequent transport to cellular lysosomes are critical factors that substantially influence ADC efficacy. However, internalization capacity of the GD2-specific antibodies and mechanisms of endocytosis of their complexes with GD2 have been insufficiently characterized. This study investigated internalization mechanisms of the ganglioside GD2 complexes with several of the most relevant GD2-specific antibody formats, namely full-length antibodies, minibodies, and scFv fragments. It was demonstrated that all used antibody variants successfully internalize into the GD2-positive tumor cells and enter their lysosomal compartments. Full-length antibodies and minibodies exhibited high endocytosis efficiency in the GD2-positive cells, occurring through several pathways, primarily macropinocytosis and caveolae-mediated endocytosis. These findings may be of interest for the development of more effective targeted therapeutics for GD2-positive tumors.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"424 - 435"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919215","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}

{"title":"Influence of in situ Limited Proteolysis of Potato Virus X on Change in the Structure of Virions According to the Small-Angle X-Ray Scattering Data and Tritium Labeling","authors":"Alexander L. Ksenofontov,&nbsp;Maxim. V. Petoukhov,&nbsp;Georgy S. Peters,&nbsp;Alexander M. Arutyunyan,&nbsp;Lyudmila A. Baratova,&nbsp;Marina V. Arkhipenko,&nbsp;Nikolai A. Nikitin,&nbsp;Olga V. Karpova,&nbsp;Eleonora V. Shtykova","doi":"10.1134/S0006297925600279","DOIUrl":"10.1134/S0006297925600279","url":null,"abstract":"<p>Capsids of the potexvirus family virions are characterized by the presence on the surface of virions of partially disordered N-terminal protein fragments of various lengths. The present study is devoted to studying the effect of <i>in situ</i> removal of the N-terminal domain of coat protein (CP) on structural organization and physicochemical properties of the potato virus X (PVX) virions. The work considers PVX virions containing an intact Ps-form CP, as well as virions including an <i>in situ</i> degraded Pf-form devoid of 19/21 amino acid residues from the N-end (PVXΔN). Synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), tritium bombardment, and several other physicochemical methods were used in the study. Analysis of the images obtained using TEM revealed similarities in the architecture of filamentous PVX and PVXΔN virions. SAXS results demonstrated differences in organization of the capsid of PVX and PVXΔN virions: the latter was characterized by the reduced size of the ordered regions, indicating partial disruption of the structure of the viral protein framework. In addition, based on the SAXS scattering curves, parameters of the spiral packing of virions in solution were calculated, and structural modeling of particles was performed. Modeling results also indicate changes in the structure of the capsid due to removal of the ΔN-peptide. Using information about the secondary structure of the PVX model (PDB ID: 6R7G) and data from our previous studies on tritium labeling of the surface sites of PVX and PVXΔN virions, comparative analysis of the label incorporation profiles into elements of the protein secondary structure was conducted. This approach made it possible to predict localization of the ΔN-peptide above the amino acid residues of neighboring helical subunits (122-129 and 143-153) and demonstrate stabilizing role of this peptide on the overall structure of the virion. Increase in the level of labelling in the C-terminal region after removal of the ΔN-peptide also indicates decrease in the compactness of the virion. In general, the gained knowledge could be useful when using virus-like nanoparticles in biotechnology.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"413 - 423"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919185","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}

{"title":"RAGE-Mediated Effects of Formaldehyde in Alzheimer’s Disease","authors":"Ilya G. Mikhailov,&nbsp;Milana S. Mikhailova,&nbsp;Anton N. Shuvaev,&nbsp;Yana V. Gorina,&nbsp;Olga S. Belozor","doi":"10.1134/S0006297924604593","DOIUrl":"10.1134/S0006297924604593","url":null,"abstract":"<p>Alzheimer’s disease (AD) remains an incurable pathology with a huge socio-economic impact. One of the known mechanisms of AD pathogenesis is deposition of amyloid plaques as a result of beta-amyloid (Aβ) accumulation. The receptor for glycation end products (RAGE) plays an important role in the Aβ transport across the blood-brain barrier. Ligand interaction with RAGE regulates the expression of the amyloid precursor protein (APP), which plays a key role in the Aβ accumulation. In this review, we discuss the biochemical mechanisms underlying the toxic effects of exogenous formaldehyde in the hippocampus leading to the insulin resistance development, as well as molecular mechanisms of neuroinflammation contributing to the upregulation of RAGE expression. Accumulation of endogenous formaldehyde in the body can be a result of impaired metabolism. However, accumulation of exogenous formaldehyde has much more acute and dangerous consequences. Formaldehyde is one of the most important toxins; its maximum permissible concentration (MPC) is exceeded in many cities of Russia, as well as in the countries of East, South, and Southeast Asia, Central Africa, and North and South Americas. Formaldehyde plays an important role in the pathogenesis of neurodegenerative diseases, as its mechanism of action is closely linked to the increased Aβ accumulation. In people more susceptible to Aβ accumulation (due to age or genetic predisposition), exposure to exogenous formaldehyde may contribute to this process. The role of formaldehyde in neurodegenerative diseases has been already investigated. It was found that the level of air pollution correlates with the incidence of hyperglycemia, but the detailed mechanism of the following development of neurodegeneration remains unclear. This review highlights the importance of studying the relationship between environmental toxins and neurodegenerative diseases, which may lead to the development of therapeutic approaches for the protection of neurons from the effects of toxic substances in individuals susceptible to neurodegenerative diseases.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"334 - 348"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919188","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}

{"title":"Interrelationship between the Non-Vesicular Transport of Sterols and Their Distribution between the Rafts and the Non-Raft Phase of the Plasma Membrane","authors":"Svyatoslav S. Sokolov,&nbsp;Anna N. Zyrina,&nbsp;Sergey A. Akimov,&nbsp;Fedor F. Severin","doi":"10.1134/S0006297924604313","DOIUrl":"10.1134/S0006297924604313","url":null,"abstract":"<p>Sterols significantly affect the barrier properties of the membrane, which might explains the fact that their concentration is maximal in the plasma membrane (PM). Together with sphingolipids, sterols form rafts, i.e., bilayer regions whose physicochemical properties differ from those of the surrounding PM. The presence of rafts allows membrane proteins to choose the lipid environment optimal for their functioning (in terms of thickness, rigidity, spontaneous curvature, and lateral pressure profile of the bilayer). The ratio between sterols and sphingolipids in the rafts is close to stoichiometric. Theoretically, excess sterol outside the rafts can critically reduce the degree of order of membrane phospholipids. Sterols are synthesized in the endoplasmic reticulum (ER). The active (against the concentration gradient) transport of sterols from the ER to the PM is driven by proteins of the Osh family, while Lam proteins provide passive reverse transport of sterols from the PM to the ER. Inactivation of Osh proteins does not reduce the total level of sterols in the PM but reduces the rate of their movement inside the PM (the mechanisms underlying this effect remains unclear). Therefore, the vesicular transport of sterols from the ER to the PM is probably more active than the non-vesicular transport carried out by Osh proteins. Since sterols are more rigidly anchored and less sterically accessible in the rafts than outside them, we suggested that Lam proteins transport excess sterols from the non-raft phase of the PM to the ER, and Osh proteins return them back to the PM. In this way, the mutual activity of the Osh and lam proteins provides the rotation of sterols between the non-raft fraction of the PM and rafts, with the enrichment of the latter. It is possible that with a decrease in the sterol concentration in the non-raft fraction of the membrane, the rate of the Lam-dependent transport decreases since the degree of order of phospholipids and, consequently, the strength of retention of sterol molecules in the membrane increases, which might represent a mechanisms maintaining the concentration and distribution of sterols in the PM.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"90 3","pages":"321 - 333"},"PeriodicalIF":2.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919262","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}