Biochemistry Biochemistry最新文献_第10页

Accessibility of Carboxypeptidase A-bound Zinc to Chelation Correlates with an Intermediate State in the Protein's Unfolding Pathway. 羧肽酶a结合锌螯合的可及性与蛋白质展开途径的中间状态相关。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-03-10 DOI: 10.1021/acs.biochem.4c00517

Danica L Goulet, Matthew W Bignucolo, Stefan Siemann

{"title":"Accessibility of Carboxypeptidase A-bound Zinc to Chelation Correlates with an Intermediate State in the Protein's Unfolding Pathway.","authors":"Danica L Goulet, Matthew W Bignucolo, Stefan Siemann","doi":"10.1021/acs.biochem.4c00517","DOIUrl":"10.1021/acs.biochem.4c00517","url":null,"abstract":"In view of the emerging role of metal ions in improper protein folding (a phenomenon associated with a variety of diseases), new tools to characterize structural changes that accompany folding transitions are highly sought. Using a combination of fluorescence spectroscopy and studies involving the chromophoric chelator 4-(2-pyridylazo)resorcinol (PAR), we here show that the prototypical zinc protease carboxypeptidase A (CPA) unfolds in the presence of guanidine hydrochloride via a previously unidentified folding intermediate that resembles a molten globular state and retains the zinc ion. The spontaneous dissociation of the metal ion from CPA was observed only upon transition of the intermediate to the fully unfolded state of the protein. Furthermore, an analysis of zinc ion binding during CPA unfolding using PAR revealed the intermediate state to directly correlate with the ability of the chelator to gain access to the active site and to associate with the protein-bound metal ion. This observation is indicative of CPA's active site being PAR-inaccessible in the native state but becoming PAR-accessible in the folding intermediate. Taken together, the current study demonstrates the usefulness of PAR as a simple spectrophotometric tool to assess structural changes during the unfolding of CPA and potentially other zinc proteins. Hence, zinc accessibility probes (ZAPs) such as PAR may find utility in gaining further insight into the mechanism(s) of metalloprotein folding.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1244-1256"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Design of Mimetic Antibodies Targeting the SARS-CoV-2 Spike Glycoprotein Based on the GB1 Domain: A Molecular Simulation and Experimental Study 基于GB1结构域的SARS-CoV-2刺突糖蛋白模拟抗体设计：分子模拟与实验研究

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-17 DOI: 10.1021/acs.biochem.4c0067110.1021/acs.biochem.4c00671

Anderson A. E Santo, Aline Reis, Anderson A. Pinheiro, Paulo I. da Costa* and Gustavo T. Feliciano*,

{"title":"Design of Mimetic Antibodies Targeting the SARS-CoV-2 Spike Glycoprotein Based on the GB1 Domain: A Molecular Simulation and Experimental Study","authors":"Anderson A. E Santo, Aline Reis, Anderson A. Pinheiro, Paulo I. da Costa* and Gustavo T. Feliciano*, ","doi":"10.1021/acs.biochem.4c0067110.1021/acs.biochem.4c00671","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00671https://doi.org/10.1021/acs.biochem.4c00671","url":null,"abstract":"In the context of fast and significant technological transformations, it is natural for innovative artificial intelligence (AI) methods to emerge for the design of bioactive molecules. In this study, we demonstrated that the design of mimetic antibodies (MA) can be achieved using a combination of software and algorithms traditionally employed in molecular simulation. This combination, organized as a genetic algorithm (GA), has the potential to address one of the main challenges in the design of bioactive molecules: GA convergence occurs rapidly due to the careful selection of initial populations based on intermolecular interactions at antigenic surfaces. Experimental immunoenzymatic tests prove that the GA successfully optimized the molecular recognition capacity of one of the MA. One of the significant results of this study is the discovery of new structural motifs, which can be designed in an original and innovative way based on the MA structure itself, eliminating the need for preexisting databases. Through the GA developed in this study, we demonstrated the application of a new protocol capable of guiding experimental methods in the development of new bioactive molecules.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1541–1549 1541–1549"},"PeriodicalIF":2.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.4c00671","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Monitoring Molecular Interactions with Cell Membranes Using Time-Dependent Second Harmonic Generation Microscopy 利用随时间变化的二次谐波生成显微镜监测分子与细胞膜的相互作用

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-14 DOI: 10.1021/acs.biochem.4c0030210.1021/acs.biochem.4c00302

Prakash Hamal, Sushant P. Sahu, Peter P. Piers, Huy Nguyen, Shashank S. Kamble, Robin L. McCarley, Manas R. Gartia* and Louis H. Haber*,

{"title":"Monitoring Molecular Interactions with Cell Membranes Using Time-Dependent Second Harmonic Generation Microscopy","authors":"Prakash Hamal, Sushant P. Sahu, Peter P. Piers, Huy Nguyen, Shashank S. Kamble, Robin L. McCarley, Manas R. Gartia* and Louis H. Haber*, ","doi":"10.1021/acs.biochem.4c0030210.1021/acs.biochem.4c00302","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00302https://doi.org/10.1021/acs.biochem.4c00302","url":null,"abstract":"Time-resolved second harmonic generation (SHG) microscopy is used to investigate the physicochemical interactions between positively charged, hydrophobic, drug-like molecules and the plasma membrane of human cells (nonsmall cell lung cancer, H596). In the present study, molecular adsorption and transport of the cationic molecules, malachite green (MG) and malachite green isothiocyanate (MGITC), are studied in real time in living H596 cells and in dead, fixed H596 cells. MGITC is shown to have stronger adsorption and more rapid transport kinetics as compared to MG due to increased dipole–dipole interactions. Additionally, MGITC is found to have faster adsorption and transport kinetics in living H596 cells in comparison to fixed H596 cells, as well as higher dispersity in transport rate, pointing to changes in the nature of the plasma membrane or its integrity. Overall, the findings highlight the importance of electrostatic interactions, chemical functional groups, and cell integrity in molecular translocation dynamics across cell membranes.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1476–1483 1476–1483"},"PeriodicalIF":2.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.biochem.4c00302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Impact of Cancer-Associated PKM2 Mutations on Enzyme Activity and Allosteric Regulation: Structural and Functional Insights into Metabolic Reprogramming 癌症相关PKM2突变对酶活性和变构调节的影响：代谢重编程的结构和功能见解

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-13 DOI: 10.1021/acs.biochem.5c0000910.1021/acs.biochem.5c00009

Saurabh Upadhyay*, Mohit Bhardwaj, Sivakumar Prasanth Kumar, Shumayila Khan, Ashwani Kumar and Md. Imtaiyaz Hassan,

{"title":"Impact of Cancer-Associated PKM2 Mutations on Enzyme Activity and Allosteric Regulation: Structural and Functional Insights into Metabolic Reprogramming","authors":"Saurabh Upadhyay*, Mohit Bhardwaj, Sivakumar Prasanth Kumar, Shumayila Khan, Ashwani Kumar and Md. Imtaiyaz Hassan, ","doi":"10.1021/acs.biochem.5c0000910.1021/acs.biochem.5c00009","DOIUrl":"https://doi.org/10.1021/acs.biochem.5c00009https://doi.org/10.1021/acs.biochem.5c00009","url":null,"abstract":"Mammalian pyruvate kinase M2 (PKM2) is a key regulator of glycolysis and is highly expressed in proliferative tissues including tumors. Mutations in PKM2 have been identified in various cancers, but their effects on enzyme activity and regulation are not fully understood. This study investigates the structural and functional effects of cancer-associated PKM2 mutations on enzyme kinetics, allosteric regulation, and oligomerization. Using computational modeling, X-ray crystallography, and biochemical assays, we demonstrated how these mutations impact PKM2 activity, substrate binding, and allosteric activation via fructose-1,6-bisphosphate (FBP), contributing to altered enzyme function. In this study, we characterized four cancer-associated PKM2 mutations (P403A, C474S, R516C, and L144P) using computational, structural, and biochemical approaches. Computational modeling revealed disruptions in allosteric signaling pathways, particularly affecting the communication between regulatory sites and the active site. X-ray crystallography demonstrated local conformational changes in the hinge and FBP-binding regions, leading to a shift from the active tetrameric state to a less active dimeric state, particularly in the C474S and R516C mutants. The mutants exhibited reduced maximal velocity, reduced substrate affinity, and altered activation by the allosteric activator fructose-1,6-bisphosphate (FBP). Under alkaline pH conditions, mimicking the tumor microenvironment, these mutations further destabilized the PKM2 oligomeric state, favoring the formation of lower-order species. Our findings suggest that PKM2 is highly sensitive to mutations, and these alterations may contribute to metabolic reprogramming in cancer cells by impairing its enzymatic regulation.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1463–1475 1463–1475"},"PeriodicalIF":2.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Cell-Penetrating Cyclic and Disulfide-Rich Peptides Are Privileged Molecular Scaffolds for Intracellular Targeting 细胞穿透环和富含二硫的肽是细胞内靶向的优越分子支架

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-13 DOI: 10.1021/acs.biochem.4c0084510.1021/acs.biochem.4c00845

Sónia Troeira Henriques, Nicole Lawrence, Meng-Wei Kan, Lara R. Malins and David J. Craik*,

{"title":"Cell-Penetrating Cyclic and Disulfide-Rich Peptides Are Privileged Molecular Scaffolds for Intracellular Targeting","authors":"Sónia Troeira Henriques, Nicole Lawrence, Meng-Wei Kan, Lara R. Malins and David J. Craik*, ","doi":"10.1021/acs.biochem.4c0084510.1021/acs.biochem.4c00845","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00845https://doi.org/10.1021/acs.biochem.4c00845","url":null,"abstract":"Peptides that have a head-to-tail cyclic backbone tend to be more stable than linear peptides, as do peptides that contain one or more cross-linking disulfide bond. Some of these cyclic and/or disulfide rich peptides have been reported to penetrate cells. These include peptides from a wide range of natural sources, including plants, spiders, crabs, and humans. In this review we describe the structures and biophysical properties of a selected set of such peptides that have been studied in our laboratories. We further describe how they can be engineered to enhance their stability and cellular uptake, and to fine-tune selective cell entry and activity toward intracellular therapeutic targets. Examples of targets described include intracellular protein–protein interactions implicated in cancer, intracellular malarial parasites and intracellular bacterial targets. In addition to the important advances being made with these nature-inspired peptides, the rapid strides in machine learning and artificial intelligence seen over recent years promise to accelerate the use of de novo design methods to produce peptides that are able to pass through biological membranes. We describe examples where such approaches have been used to design macrocyclic peptides and peptide–drug conjugates that can penetrate cell membranes and even have significant oral bioavailability in some cases.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1437–1449 1437–1449"},"PeriodicalIF":2.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Mechanism of Conformational Selection of tRNAArg2 by Bacterial Deaminase TadA 细菌脱氨酶TadA作用下tRNAArg2构象选择的机制

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-12 DOI: 10.1021/acs.biochem.4c0064910.1021/acs.biochem.4c00649

Jessy Mariam, Sini Porathoor and Ruchi Anand*,

{"title":"Mechanism of Conformational Selection of tRNAArg2 by Bacterial Deaminase TadA","authors":"Jessy Mariam, Sini Porathoor and Ruchi Anand*, ","doi":"10.1021/acs.biochem.4c0064910.1021/acs.biochem.4c00649","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00649https://doi.org/10.1021/acs.biochem.4c00649","url":null,"abstract":"Base editing is a common mechanism by which organisms expand their genetic repertoire to access new functions. Here, we explore the mechanism of tRNA recognition in the bacterial deaminase TadA, which exclusively recognizes tRNAArg2 and converts the wobble base adenosine (A34) to inosine. We quantitatively evaluate the dynamics of tRNA binding by incorporating the fluorescent adenine analogue 2-aminopurine (2-AP) at position 34 in the wobble base of the anticodon loop. Time-resolved fluorescence and anisotropy studies revealed that the recognition process is finely tuned. Mutations in residues directly involved in facilitating deamination, such as E55A and N42A, showed a minimal impact on binding dynamics. In contrast, mutations in the “capping residues”, notably R149, unique to prokaryotic TadAs and located 12–15 Å away from the catalytic center, significantly disrupted binding and consequently catalytic activity. The capping residues play a critical role in enabling tRNA recognition, thereby underscoring their importance in enzyme function. Moreover, for effective catalysis, peripheral positively charged residues (R70, R94) that are part of the adjacent subunit in the dimeric assembly are important to splay out the tRNA, assisting in A34 attaining a flipped-out conformation. Perturbations in these extended regions, although 15–20 Å away from the active site, disrupt the binding dynamics and consequently the function, emphasizing the fine regulation of the tRNA recognition process. Analysis reveals that the C-terminal end of the extended helix where R149 is positioned, acts as a selectivity filter imparting exclusivity toward the deamination of tRNAArg2 by TadA.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1530–1540 1530–1540"},"PeriodicalIF":2.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Specific Interaction between a Fluoroquinolone Derivative, KG022, and RNAs with a Single Bulge. 氟喹诺酮衍生物KG022与单凸起rna的特异性相互作用。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-11 DOI: 10.1021/acs.biochem.4c00669

Rika Ichijo, Gota Kawai

引用次数: 0

Mechanism of Annealing of Complementary DNA Strands by the Single-Stranded DNA Binding Protein of Bacteriophage T7 噬菌体T7单链DNA结合蛋白退火互补DNA链的机制

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-11 DOI: 10.1021/acs.biochem.4c0073010.1021/acs.biochem.4c00730

Seung-Joo Lee, Charlotte Ferguson, Sebastian Urbano, Jaehun Lee, Peter Jeong, Meghana Cheela, Hitoshi Mitsunobu, Bin Zhu, Ashmita Prajapati, Charles C. Richardson* and Alfredo J. Hernandez*,

{"title":"Mechanism of Annealing of Complementary DNA Strands by the Single-Stranded DNA Binding Protein of Bacteriophage T7","authors":"Seung-Joo Lee, Charlotte Ferguson, Sebastian Urbano, Jaehun Lee, Peter Jeong, Meghana Cheela, Hitoshi Mitsunobu, Bin Zhu, Ashmita Prajapati, Charles C. Richardson* and Alfredo J. Hernandez*, ","doi":"10.1021/acs.biochem.4c0073010.1021/acs.biochem.4c00730","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00730https://doi.org/10.1021/acs.biochem.4c00730","url":null,"abstract":"Gp2.5, an essential single-stranded DNA-binding protein encoded by bacteriophage T7, is integral to various steps of DNA metabolism. Unlike other single-stranded DNA binding proteins, it greatly facilitates the annealing of complementary DNA strands. Gp2.5 efficiently anneals DNA duplexes as short as 30 base pairs: efficient annealing occurs at a 100-fold lower concentration of complementary strands than that required in the absence of gp2.5. Additionally, gp2.5 selectively promotes DNA annealing with no observed effect on RNA or DNA hybrids. Kinetic studies show a substantial increase in the annealing rate, with gp2.5 accelerating the process by 30-fold compared with spontaneous annealing. Gp2.5 tolerates mismatches and unpaired loops within DNA, facilitating annealing in sequences with slight imperfections. FRET analysis demonstrates that gp2.5 brings strands of ssDNA into close proximity irrespective of their complementarity, likely through interactions between gp2.5 molecules. A unique long α helix A in gp2.5 is critical for its annealing activity: deletions of helix A impair DNA annealing without affecting DNA replication functions.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1550–1559 1550–1559"},"PeriodicalIF":2.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Binding Sites of a PET Ligand in Tau Fibrils with the Alzheimer’s Disease Fold from 19F and 13C Solid-State NMR 来自19F和13C固体核磁共振的阿尔茨海默病Tau原纤维中PET配体的结合位点

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-11 DOI: 10.1021/acs.biochem.5c0001610.1021/acs.biochem.5c00016

Frida N. Angehrn, Pu Duan, Jia Yi Zhang and Mei Hong*,

{"title":"Binding Sites of a PET Ligand in Tau Fibrils with the Alzheimer’s Disease Fold from 19F and 13C Solid-State NMR","authors":"Frida N. Angehrn, Pu Duan, Jia Yi Zhang and Mei Hong*, ","doi":"10.1021/acs.biochem.5c0001610.1021/acs.biochem.5c00016","DOIUrl":"https://doi.org/10.1021/acs.biochem.5c00016https://doi.org/10.1021/acs.biochem.5c00016","url":null,"abstract":"Aggregation of the tau protein into cross-β amyloid fibrils is a hallmark of Alzheimer’s disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. Here, we report the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold. Using solid-state NMR 13C–19F rotational-echo double-resonance (REDOR) experiments, we measured the proximity of protein residues to the fluorine atom of the ligand. These data indicate that PI-2620 binds at two main locations in the concave interior of the C-shaped structure. Molecular docking simulations constrained by these REDOR data identified five binding poses at these two locations. In addition, 2D 13C–13C correlation NMR spectra indicate that PI-2620 decreased the intensities of residues at the protofilament interfaces, indicating that the ligand disordered the filament packing. Quantitative analysis of the 19F NMR spectra indicates that PI-2620 binds these AD-fold tau fibrils with a stoichiometry of ∼20 mol %, in which 10 mol % are immobilized and the rest are mobile. These results provide experimental constraints to the interaction of this second-generation PET tracer with tau fibrils adopting the AD fold and should be useful for the development of future imaging agents with improved stoichiometry and specificity for AD tau.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1624–1635 1624–1635"},"PeriodicalIF":2.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Structure of the CD33 Receptor and Implications for the Siglec Family CD33受体的结构及其对Siglec家族的影响

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-11 DOI: 10.1021/acs.biochem.4c0086410.1021/acs.biochem.4c00864

Han N. Vu, Alan J. Situ, Xuhang Dai and Tobias S. Ulmer*,

{"title":"Structure of the CD33 Receptor and Implications for the Siglec Family","authors":"Han N. Vu, Alan J. Situ, Xuhang Dai and Tobias S. Ulmer*, ","doi":"10.1021/acs.biochem.4c0086410.1021/acs.biochem.4c00864","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00864https://doi.org/10.1021/acs.biochem.4c00864","url":null,"abstract":"In the innate immune system, the CD33 receptor modulates microglial activity. Its downregulation promises to slow Alzheimer’s disease, and it is already targeted in blood cancers. The mechanism underlying CD33 signaling is unresolved. Starting from the available crystal structure of its extracellular IgV-IgC1 domains, we have assembled a model of the human CD33 receptor by characterizing the oligomerization and structure of IgC1, transmembrane, and cytosolic domains in solution. IgC1 homodimerizes via intermolecular β-strand pairing and packing. In contrast, the 21-residue transmembrane helix of CD33 appears monomeric and straight, with a conserved thin neck and thick belly appearance followed by a positively charged cytosolic patch. The cytosolic domain is dynamically unstructured. Sequence alignment and AlphaFold models indicate that IgC domains in the family of human Siglecs, to which CD33 belongs, are surprisingly variable. Only Siglec-6 is identified to analogously dimerize via IgC1. Our CD33 structural model suggests that the receptor is not signaling via a monomer–dimer shift. Rather, we propose that, aided but also constrained by dimerization, multivalent ligands may concentrate the receptor transmembrane and cytosolic domains sufficiently to trigger colocalization with an activating kinase.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1450–1462 1450–1462"},"PeriodicalIF":2.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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