Biochemical Journal最新文献_第3页

The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond. 蛋白酶疗法的作用扩展（2012-2026）：从替代疗法到免疫系统调节及其他。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20260152

Sage E Nelson, Samantha G Martinusen, Raymond Pho, Lawton F Long, Carl A Denard

{"title":"The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.","authors":"Sage E Nelson, Samantha G Martinusen, Raymond Pho, Lawton F Long, Carl A Denard","doi":"10.1042/BCJ20260152","DOIUrl":"10.1042/BCJ20260152","url":null,"abstract":"Proteases are powerful therapeutic agents, offering unique advantages over conventional small molecules and biologics through their ability to directly and precisely cleave and (de)activate their protein targets. Since the early 1990s, FDA-approved protease therapeutics have served as replacement therapies for hematological disorders, as enzyme supplements for digestive disorders, and as treatments for neuromuscular disorders. Recent developments have expanded the use of native proteases to modulate antibody responses, improve transplant outcomes, and treat rare conditions with high unmet needs. Despite challenges such as immunogenicity and substrate specificity, the therapeutic landscape of proteases is being redefined by innovations in enzyme engineering and discovery. These advances, combined with targeted delivery strategies and improved stability, are reshaping proteases into precise and adaptable therapeutic agents. Rather than being limited to traditional uses, proteases are increasingly recognized for their potential to address complex conditions such as viral infections, neurodegeneration, and fibrosis, among others. With continued development, proteases are positioned to become a versatile and robust class of biologics with expanding clinical relevance. The present review explores the evolving landscape of protease therapeutics, focusing on their clinical applications, immune-modulatory capabilities, and future potential in precision medicine. This review provides a timely update to the comprehensive article \"Proteases as Therapeutics\" by Craik, Page, and Madison, published in the Biochemical Journal in 2011.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"483 7","pages":"1173-1191"},"PeriodicalIF":3.9,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154991","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

An S752D activation loop mutation dynamically primes Muscle-Specific Kinase for activation. S752D激活环突变动态启动肌肉特异性激酶（MuSK）的激活。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20260159

Jakob J Prömer, James W Murphy, Mark A Lemmon, Yuko Tsutsui, Ruth Herbst

{"title":"An S752D activation loop mutation dynamically primes Muscle-Specific Kinase for activation.","authors":"Jakob J Prömer, James W Murphy, Mark A Lemmon, Yuko Tsutsui, Ruth Herbst","doi":"10.1042/BCJ20260159","DOIUrl":"10.1042/BCJ20260159","url":null,"abstract":"Muscle-Specific Kinase (MuSK) is a receptor tyrosine kinase essential for neuromuscular junction (NMJ) formation and maintenance, yet its regulation remains poorly understood. Crystallographic studies of wild-type MuSK revealed an autoinhibited conformation with tyrosines in the activation loop (A-loop) anchored within the catalytic cleft to stabilize the closed, inactive conformation. We showed previously that additional phosphorylation of an A-loop serine may 'prime' MuSK for activation to sensitize it to ligand(s) in certain settings. Here, we employed crystallography, biochemical assays, and hydrogen-deuterium exchange and mass spectrometry (HDX-MS) to test this hypothesis. We found that introducing a phosphomimetic S752D mutation disrupts autoinhibitory A-loop interactions to increase ATP-binding affinity and catalytic turnover. Using HDX-MS, we further observed that the S752D mutation increases A-loop structural flexibility to relieve autoinhibition. The S752D mutation also stabilizes the juxtamembrane NPXY motif region, a docking site for the adaptor Dok7, possibly priming MuSK for downstream signaling. Together, these findings reveal dynamic transitions that underlie relief of MuSK autoinhibition and provide a mechanistic framework for understanding MuSK activation at the NMJ.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1221-1235"},"PeriodicalIF":3.9,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155002","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

Difference and similarity between the ubiquitous secretory pathway Ca2+-ATPases, SERCA2b, and SPCA1a. 无处不在的Ca2+- atp酶、SERCA2b和SPCA1a分泌途径的异同。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/bcj20250360

Yuxia Zhang,Kenji Inaba

{"title":"Difference and similarity between the ubiquitous secretory pathway Ca2+-ATPases, SERCA2b, and SPCA1a.","authors":"Yuxia Zhang,Kenji Inaba","doi":"10.1042/bcj20250360","DOIUrl":"https://doi.org/10.1042/bcj20250360","url":null,"abstract":"P1B-type and P2-type ATPases play fundamental roles in maintaining intracellular metal ion homeostasis, which is essential for various cellular processes including protein folding, trafficking and signaling. SERCA2b, a member of the P2A-type subfamily, pumps Ca2+ into the endoplasmic reticulum (ER) lumen, whereas SPCA1a, which also belongs to the P2A-type subfamily, mediates the transport of both Ca2+ and Mn2+ into the Golgi apparatus. With recent advances in their structural studies, researchers, including ourselves, have thoroughly characterized high-energy intermediates of these two Ca2+ pumps, which likely serve to facilitate transitions during the catalytic cycle by conformationally bridging the preceding and subsequent reaction states. In addition, we present a comparative analysis of the differences in cytosolic-domain rearrangements and transmembrane helix movements during the Ca2+ transport cycle, highlighting distinct metal ion transport mechanisms and kinetics between SERCA2b and SPCA1a. Notably, we identify unique structural elements involved in Ca2+ release and propose a potential SPCA1a-specific Ca2+ release pathway. The present review provides insights into the subfamily-specific variations in Ca2+ pump mechanisms.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"11 1","pages":"1319-1335"},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148313655","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

Photocross-linking activity-based probes to capture the dynamics of ubiquitin RING E3 ligase interactions. 基于光交联活性的探针捕捉泛素环E3连接酶相互作用的动力学。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20260213

Sarah F Chandler, Michael H Tatham, Emma Branigan, Mark A Nakasone, Nikolai Makukhin, Alessio Ciulli, Ronald T Hay

{"title":"Photocross-linking activity-based probes to capture the dynamics of ubiquitin RING E3 ligase interactions.","authors":"Sarah F Chandler, Michael H Tatham, Emma Branigan, Mark A Nakasone, Nikolai Makukhin, Alessio Ciulli, Ronald T Hay","doi":"10.1042/BCJ20260213","DOIUrl":"10.1042/BCJ20260213","url":null,"abstract":"Almost all cellular processes are influenced by ubiquitination. A large family of enzymes known as E3 ligases provides the specificity for ubiquitination, with the largest class among them, the Really Interesting New Gene (RING) E3s, comprising over 600 members in humans. RING E3s facilitate transfer of ubiquitin (Ub) to substrates by constraining the highly dynamic E2-Ub thioester linkage to be primed for attack from the substrate nucleophile. We have established a workflow that uses an N-maleimido diazirine (NMD) photoactivatable cross-linker attached to ubiquitin that, once stably linked to the active site of an E2, creates an activity-based probe (ABP) to monitor interactions with E3 ligases. Cross-linking mass spectrometry using the NMD-Ub-E2 ABP identified regions of interaction between ubiquitin and a selection of different RING E3s, which not only agreed with existing crystal structures, but was also used to evaluate in silico structural models of complexes yet to be resolved by conventional means. The cross-linking data also provided insight into domains of conformational flexibility which likely adopt multiple configurations in solution and which are challenging to monitor by other methods. NMD-Ub-E2 ABPs offer great potential to explore the ensemble conformations of E2-E3 complexes in solution and have scope for applications beyond the ubiquitin system.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1115-1130"},"PeriodicalIF":3.9,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866629","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

Retraction: A new Mad2-interacting domain of Cdc20 is critical for the function of Mad2-Cdc20 complex in the spindle assembly checkpoint. 摘要：Cdc20的一个新的mad2相互作用结构域对Mad2-Cdc20复合物在纺锤体组装检查点中的功能至关重要。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20051914_RET

Susanta Roychoudhury, Gourish Mondal, Rathindra N Baral

引用次数: 0

Correction: Exposure of HL-60 human leukaemic cells to 4-hydroxynonenal promotes the formation of adduct(s) with α-enolase devoid of plasminogen binding activity. 更正：HL-60人白血病细胞暴露于4-羟基壬烯醛可促进与缺乏纤溶酶原结合活性的α-烯醇化酶的加合物的形成。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20090564_COR

Giuseppina Barrera, Fabrizio Gentile, Stefania Pizzimenti, Alessia Arcaro, Piergiorgio Pettazzoni, Rosalba Minelli, Daniela D'Angelo, Gianfranco Mamone, Pasquale Ferranti, Cristina Toaldo, Gianpaolo Cetrangolo, Silvestro Formisano, Mario U Dianzani, Koji Uchida, Chiara Dianzani

引用次数: 0

Retraction: A non-catalytic function of carbonic anhydrase IX contributes to the glycolytic phenotype and pH regulation in human breast cancer cells. 撤回：碳酸酐酶IX的非催化功能有助于人类乳腺癌细胞的糖酵解表型和pH调节。

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20190177_RET

Susan Frost, Mam Y Mboge, Zhijuan Chen, Daniel Khokhar, Alyssa Wolff, Lingbao Ai, Coy D Heldermon, Murat Bozdag, Fabrizio Carta, Claudiu T Supuran, Kevin D Brown, Robert McKenna, Christopher J Frost

引用次数: 0

A molecular perspective on dimethylarginine dimethylaminohydrolases structure and function. 二甲基精氨酸二甲基氨基水解酶结构与功能的分子研究。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/bcj20260122

Luana Ruta,Mirco Dindo,Ilaria Bellezza,Silvia Grottelli,Natalia Jarzebska,Elisa Bianconi,Antonio Macchiarulo,Barbara Cellini,Roman N Rodionov

{"title":"A molecular perspective on dimethylarginine dimethylaminohydrolases structure and function.","authors":"Luana Ruta,Mirco Dindo,Ilaria Bellezza,Silvia Grottelli,Natalia Jarzebska,Elisa Bianconi,Antonio Macchiarulo,Barbara Cellini,Roman N Rodionov","doi":"10.1042/bcj20260122","DOIUrl":"https://doi.org/10.1042/bcj20260122","url":null,"abstract":"Nitric oxide (NO) is a central signaling molecule that regulates vascular tone, neurotransmission, and immune function. NO production from L-arginine by nitric oxide synthase (NOS) must be tightly controlled, as excess NO contributes to oxidative and nitrosative stress. Asymmetric dimethylarginine (ADMA) and monomethylarginine (L-NMMA) are endogenous NOS inhibitors whose accumulation leads to cardiovascular, renal, and neurodegenerative diseases. Dimethylarginine dimethylaminohydrolase (DDAH) converts ADMA and NMMA to L-citrulline and dimethylamine or monomethylamine, respectively, thereby controlling NO bioavailability. Two DDAH isoforms are present in humans, namely, DDAH1 and DDAH2. DDAH1 has a demonstrated role in the catabolism of ADMA, while DDAH2 appears to be functionally divergent, playing potential regulatory and signaling roles. Structural analyses reveal that, despite a conserved α/β-propeller architecture, the different biochemical properties of the two isoforms depend on key amino acid substitutions within the active site. Dysregulation of DDAH1 leads to pathological ADMA accumulation, linking impaired enzyme function to endothelial dysfunction and oxidative stress. Consequently, DDAH1 represents an emerging therapeutic target, and several substrate analogues, small molecules, and natural ligands have been identified as inhibitors. On the other hand, the assessment of DDAH2 function is still to be defined. The present review summarizes current molecular, biochemical, and structural insights into DDAH isoforms and discusses their potential as pharmacological targets for diseases associated with altered NO signaling.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"36 1","pages":"1237-1252"},"PeriodicalIF":4.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148305032","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

Non-canonical and constitutive activation of small GTPases: more than an exception to the rule? 小gtpase的非规范和本构激活：不仅仅是规则的例外？

IF 3.9 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/BCJ20250137

Jasmine Kiers, Peter L Hordijk

{"title":"Non-canonical and constitutive activation of small GTPases: more than an exception to the rule?","authors":"Jasmine Kiers, Peter L Hordijk","doi":"10.1042/BCJ20250137","DOIUrl":"10.1042/BCJ20250137","url":null,"abstract":"The superfamily of small GTPases comprises over 150 members, clustered in different families (e.g., Ras, Rab, Rho), that together are essential for a wide range of cellular functions. Most GTPases behave as molecular on/off switches, with regulatory proteins controlling their cycling between the GDP-bound, inactive form and the GTP-bound, active form. However, there is a substantial number of small GTPases that do not adhere to this canonical mode of regulation. This can result from key sequence differences that maintain these GTPases mostly in the GTP-bound form. Alternatively, specific post-translational modifications, including ubiquitination or alternative lipidation, can activate these GTPases, for example, due to interference with their intrinsic GTP hydrolysis capacity. Such 'atypical' GTPases are often constitutively active and are furthermore characterized by fast turnover. Consequently, their output is much more a function of their expression levels, with proteasomal or lysosomal degradation limiting their signaling capacity. This review discusses recent insights into non-canonical activation of small GTPases. We also discuss modifications, in particular palmitoylation, which allows otherwise canonical GTPases to become (constitutively) active, escaping their usual regulatory mechanisms. Finally, we discuss the potential biological importance of non-canonical GTPase regulation. We focus on the difference in kinetics and signal duration between canonical cycling versus non-canonical activation, and discuss differences related to fast, external stimulation (e.g., by hormones and growth factors) versus slow, intrinsic signaling, linked to altered metabolism, autophagy, or disease.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"483 7","pages":"1153-1171"},"PeriodicalIF":3.9,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13236570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155037","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

Proteolytic coordination of the OXPHOS Life Cycle. OXPHOS生命周期的蛋白水解协调。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-07-08 DOI: 10.1042/bcj20250120

Nataliia Nechytailo,Karolina Szczepanowska

引用次数: 0