Biomolecules最新文献

{"title":"Construction of an Esophageal Cancer Prognostic Model Based on Mitochondrial Energy Metabolism-Related Genes and Mechanism of INHBA in Promoting Malignant Progression via the Smad2/3 Pathway.","authors":"Jinping Li, Yi Yao, Huikai Li, Bozong Shao, Enqiang Linghu","doi":"10.3390/biom16091367","DOIUrl":"10.3390/biom16091367","url":null,"abstract":"<p><strong>Objective: </strong>Esophageal cancer (ESCA) has poor prognosis and lacks reliable biomarkers. This study aimed to construct a mitochondrial energy metabolism-related prognostic model and identify key regulatory genes.</p><p><strong>Methods: </strong>TCGA-ESCA and GSE53625 data were used as training and validation cohorts, respectively. Mitochondrial energy metabolism scores were calculated by ssGSEA. Differential expression analysis and WGCNA identified key genes, followed by consensus clustering, Cox/LASSO regression, enrichment analysis, immune infiltration, TIDE evaluation, and nomogram development. INHBA knockdown or overexpression was performed in KYSE-150 and TE-1 cells to assess malignant phenotypes, mitochondrial function, EMT markers, and Smad2/3 signaling, with SB431542 used for pathway blockade.</p><p><strong>Results: </strong>High mitochondrial energy metabolism scores predicted poorer overall survival. A total of 124 key genes were identified, and three molecular subtypes were established, with Cluster 2 showing the worst prognosis. A four-gene signature comprising COL11A1, INHBA, TNFAIP6, and POSTN stratified patients into high- and low-risk groups in both cohorts. High-risk tumors were enriched in extracellular matrix remodeling, cell adhesion, inflammatory response, hypoxia, angiogenesis, and PI3K-Akt signaling, whereas oxidative phosphorylation was more active in low-risk tumors. The high-risk group had higher TIDE scores, suggesting poorer immunotherapy response. The nomogram incorporating risk group and M stage showed limited discrimination after bootstrap correction. In vitro, INHBA promoted proliferation, migration, invasion, EMT, mitochondrial membrane potential, ATP production, and oxidative phosphorylation. SB431542 partially reversed these effects.</p><p><strong>Conclusions: </strong>This MEMRG-based model predicts ESCA prognosis and immune features. INHBA promotes ESCA progression by activating Smad2/3-mediated EMT and mitochondrial metabolic reprogramming, suggesting its potential as a prognostic biomarker and therapeutic target.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"White Adipose Tissue Contributes to Cardiac Homeostasis and Adaptation to Cardiometabolic Stress in a Sex- and Depot-Specific Manner.","authors":"Sara-Ève Thibodeau, Nicolas Le Bos, Élisabeth Walsh-Wilkinson, Emylie-Ann Labbé, Audrey Morin-Grandmont, Emmy Trahan, Mathias Zakrzewski, Jacques Couet","doi":"10.3390/biom16091364","DOIUrl":"10.3390/biom16091364","url":null,"abstract":"<p><strong>Background: </strong>White adipose tissue (WAT) is increasingly recognized as an endocrine organ involved in cardiovascular physiology. However, the specific contributions of distinct adipose depots to cardiac homeostasis and adaptation to pathological stress remain poorly understood. We investigated the consequences of visceral (VAT) or subcutaneous (SAT) lipectomy (Lpx) on cardiac phenotype in male and female C57BL/6J mice and evaluated its impact on the response to a stress-inducing heart failure with preserved ejection fraction-like phenotype.</p><p><strong>Methods: </strong>VAT or SAT depot removal was performed in young adult mice. Ten weeks later, we assessed cardiac morphology, function, circulating adipokines, and left ventricular (LV) gene expression. We then exposed separate cohorts to angiotensin II infusion combined with a high-fat diet. We also conducted experiments in ovariectomized (Ovx) females to evaluate the contribution of ovarian hormones.</p><p><strong>Results: </strong>Lpx induced marked depot- and sex-specific effects on body composition, cardiac morphology, and echocardiographic parameters. Changes in LV mass, atrial size, and diastolic indices were observed despite the absence of overt pathology. These alterations were accompanied by substantial modulation of genes involved in cardiac hypertrophy, calcium handling, extracellular matrix remodelling, and energy metabolism. VAT and SAT removal also differentially affected circulating adiponectin, leptin, and MCP-1 levels. Lpx modified the cardiac hypertrophic response to cardiometabolic stress in a sex- and depot-dependent manner. Ovx altered several of these responses and was associated with evidence of increased pulmonary congestion in VAT-lipectomized females.</p><p><strong>Conclusions: </strong>These findings show that WAT contributes to maintaining cardiac homeostasis and influences adaptation to pathological stress through mechanisms highly dependent on adipose depot location, biological sex, and ovarian hormone status.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-Adenosylmethionine-Dependent Methylation, Protein Arginine Methyltransferases and Cardiovascular Diseases.","authors":"Zi Yan, Wenhui Zhao, Naixin Zhao, Jianguo Li","doi":"10.3390/biom16091365","DOIUrl":"10.3390/biom16091365","url":null,"abstract":"<p><p>Methylation, catalyzed by a diverse family of S-adenosylmethionine (SAM)-dependent methyltransferases, is a fundamental biochemical process that regulates the function of proteins, DNA, and RNA. Among these modifications, protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), represents a critical post-translational mechanism regulating transcription, DNA repair, RNA splicing, and signal transduction. Emerging evidence highlights important roles of PRMTs in cardiovascular diseases (CVDs); however, current research is limited by several challenges, including the paradoxical and context-dependent functions of individual PRMTs and the lack of highly specific inhibitors or activators, leaving their therapeutic potential incompletely defined. This review summarizes the classification, structure, and functional characteristics of methyltransferases, with a particular focus on PRMTs and their roles in normal physiology and diverse CVDs. We integrate current knowledge to provide a comprehensive understanding of how PRMTs contribute to cardiovascular pathophysiology by methylating histones, transcription factors, and other functional proteins. Collectively, PRMTs emerge as pivotal regulators in CVD development and progression. Future studies should prioritize resolving the functional duality of specific PRMTs, developing targeted precision therapeutics, and elucidating the roles of less-characterized family members in CVDs.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding Tryptase Physiology, Clinical Significance, and Diagnostic Applications: Where Do We Stand?","authors":"Mara De Amici, Ivan Taietti, Riccardo Castagnoli, Grazia Bossi, Simone Foti Randazzese, Alessia Marseglia, Silvia Maria Elena Caimmi, Amelia Licari","doi":"10.3390/biom16091360","DOIUrl":"10.3390/biom16091360","url":null,"abstract":"<p><p>Tryptase is the principal biomarker of mast cell (MC) burden and activation, routinely used in the diagnosis and management of MC-related disorders. Beyond its established role in confirming anaphylaxis, serum tryptase has gained increasing relevance in the diagnosis of systemic mastocytosis, hereditary α-tryptasemia (HαT), cutaneous mastocytosis, and selected haematologic diseases. Recent advances in MC biology, tryptase genetics, and disease classification have substantially improved the interpretation of baseline and acute (event-related) tryptase measurements. In particular, validation of the \"20% + 2\" consensus formula for MC activation and the recognition of HαT as a common genetic cause of elevated baseline serum tryptase have refined diagnostic algorithms and risk-stratification strategies. This review summarizes current knowledge on tryptase physiology, laboratory assessment, and clinical significance across multiple disease settings, with particular emphasis on the interpretation of baseline serum tryptase, the diagnostic role of tryptase in anaphylaxis and mastocytosis, and emerging applications in allergy, hematology, and chronic inflammatory disorders. Understanding both the strengths and limitations of serum tryptase measurement is essential for accurate diagnosis, prognostic assessment, and personalized patient management.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outside-In Signaling as a Detonator-like Stimulus of Integrin Activation by Promoting Both Affinity and Avidity.","authors":"Naoyuki Kondo, Tatsuo Kinashi","doi":"10.3390/biom16091358","DOIUrl":"10.3390/biom16091358","url":null,"abstract":"<p><p>Integrins play a central role in a wide range of biological processes, including development, tissue homeostasis, immune responses, and disease progression. Their activation is traditionally explained by two major signaling modes: inside-out signaling, which converts integrins to ligand-competent and high-affinity states through intracellular activators, including the Rap1-talin-kindlin axis, and outside-in signaling, which transduces ligand engagement into cytoskeletal coupling and downstream signaling. Recent findings indicate that this division is incomplete. Ligand-engaged integrins can also generate spatially organized signaling platforms that feed back to enhance integrin adhesiveness <i>per se</i>. In this revised view, outside-in signaling does not merely report the completion of adhesion but can amplify both affinity, by stabilizing activator binding and high-affinity conformations, and avidity, by promoting integrin clustering and local integrin accumulation. This feedback mechanism is most extensively characterized in lymphocytes, where LFA1 (αLβ2) outside-in signaling activates Rap1 and recruits talin1 and kindlin-3, increases LFA1-ICAM1 binding stability, and promotes LFA1 transport through ATG8/LC3-associated machinery. Importantly, this ATG8/LC3-dependent process, named LAPTIN, does not represent canonical degradative autophagy but rather defines an integrin-induced LC3-associated protein transport pathway that promotes LFA1 accumulation. These observations position outside-in signaling as a potential \"detonator\" of positive-feedback activation rather than a passive consequence of ligand binding. In this review, we summarize the structural and cellular basis of affinity and avidity regulation, compare activation-promoting outside-in and related feedback mechanisms across adherent-cell, leukocyte, and platelet systems, and discuss how outside-in-based trafficking, LC3-associated protein transport, metabolic signaling, and mechanical force reveal shared regulatory principles alongside integrin-specific implementations, with potential implications for therapeutic targeting.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omics Studies in Osteoarthritis: A Review of Molecular Mechanisms and Candidate Molecules.","authors":"Yimeng Sun, Qulong Xiao, Ming Jin, Ge Liu, Qingzhong Zhang, Xiaowei Wei","doi":"10.3390/biom16091363","DOIUrl":"10.3390/biom16091363","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a joint disease of unknown etiology that can occur in joints throughout the body, especially with articular cartilage lesions of the knee joint and hip joint. Osteoarthritis not only causes joint pain, deformity, and functional impairment, but also significantly increases the risk of cardiovascular events, deep vein thrombosis in the lower limbs, and hip fractures. Up to now, there have been no specific medications available for the treatment of osteoarthritis, and the disease remains incurable. Therefore, identifying reliable biomarkers is crucial for achieving a more accurate diagnosis of OA and for guiding the development of targeted treatment strategies. In this paper, we screen and synthesize articles that performed transcriptomics and proteomics analysis on tissue or cell samples taken from osteoarthritis cartilage. We identify common differentially expressed genes (co-DEGs) and proteins (co-DEPs) in cartilage samples from knee osteoarthritis (KOA) and hip osteoarthritis (HOA) and consolidate them into candidate molecules, while systematically delineating their expression trends and underlying mechanisms at both the transcriptomic and proteomic levels. This review establishes a theoretical foundation and identifies future research directions for functional validation and clinical translation of these candidate molecules as potential biomarkers and therapeutic targets for osteoarthritis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Antioxidant Activity and Dual-Target Inhibitory Effects of Dipyridamole on α-Amylase and α-Glucosidase: Molecular Mechanisms and Molecular Dynamics Simulations.","authors":"Cong Zhao, Hongfei Liu, Yuting Shu, Jingchen Wei, Ruiqian Feng, Lina Chen, Helong Bai, Jing Wang, Dongfang Shi","doi":"10.3390/biom16091361","DOIUrl":"10.3390/biom16091361","url":null,"abstract":"<p><p>α-Amylase and α-glucosidase are complementary therapeutic targets in type 2 diabetes; simultaneous inhibition provides a dual-blockade strategy to suppress postprandial hyperglycemia. Dipyridamole, a conventional antiplatelet drug with proven anti-inflammatory, antioxidant, and antiproliferative effects and a favorable safety profile, is a candidate for repurposing. This study assessed in vitro antioxidant activity and inhibitory actions against both enzymes, and employed molecular docking, molecular dynamics simulations to elucidate mechanisms. Dipyridamole showed EC₅₀ values of 589.7 μM (ABTS+·), 652.2 μM (·OH), and 1607.1 μM (DPPH·), and IC₅₀ values of 257.6 μM (α-amylase) and 348.8 μM (α-glucosidase). Molecular docking yielded binding free energies of -6.5 and -6.0 kcal/mol for α-amylase and α-glucosidase, respectively, with binding mediated mainly by hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations revealed that, under the present simulation conditions, both the apo forms of α-amylase and α-glucosidase and their respective dipyridamole complexes exhibited relatively stable dynamical behavior throughout the course of the trajectories. Overall, dipyridamole showed not only moderate free radical scavenging capacity but also inhibitory activity against α-amylase and α-glucosidase, suggesting that this molecule may serve as a promising lead compound for further relevant drug development and functional exploration.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abdominal Bloating in the Modern Era: Pathophysiological Mechanisms and Environmental Contributors.","authors":"Andrea Piccioni, Noelia Di Bari, Marcello Candelli, Angela Saviano, Alessio Migneco, Antonio Gasbarrini, Francesco Franceschi, Veronica Ojetti","doi":"10.3390/biom16091359","DOIUrl":"10.3390/biom16091359","url":null,"abstract":"<p><p>Over the past decades, abdominal bloating has been recognized as a common gastrointestinal symptom that significantly affects the quality of life of patients and represents one of the most frequently reported manifestations of gastrointestinal disorders. Abdominal bloating has traditionally been considered a symptom with underlying functional causes, including psychological stress, metabolic disorders, and consumption of a Western-type diet. However, none of these factors fully explains its prevalence. It has been hypothesized that the high prevalence of abdominal bloating may be explained by an increased vulnerability of the digestive system, driven by alterations in the function of the intestinal barrier, as well as in neuroendocrine regulation and environmental and metabolic factors. This review incorporates recent insights into intestinal fermentation, dysbiosis, chronic low-grade inflammation, and gut-brain axis dysfunctions to propose a unified conceptual framework. In this context, chronic exposure to emerging environmental factors could reduce gastrointestinal resilience and modulate responses to fermentative and visceral stimuli. Potential environmental factors include air pollution, microplastics, and endocrine-disrupting chemicals. Overall, these findings suggest a potential role for environmental factors in the modulation of gastrointestinal physiology, although direct evidence linking environmental exposure to abdominal bloating in humans remains limited.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast Growth Factor 23 and Outcomes in Acute Heart Failure.","authors":"Arancha Martí-Martínez, Julio Núñez, Herminio López-Escribano, Rafael de la Espriella, Enrique Santas, Enrique Rodriguez-Borja, Òscar Miró, Pere Llorens, Aitor Alquézar-Arbé, Pablo Herrero-Puente","doi":"10.3390/biom16091362","DOIUrl":"10.3390/biom16091362","url":null,"abstract":"<p><p>Worsening heart failure (WHF) is a complex clinical syndrome associated with a high risk of mortality and further decompensations, characterized by fluid overload and upregulated inflammatory and fibrotic processes linked to organ dysfunction. Fibroblast growth factor 23 (FGF23) is an emerging proxy of fibrosis and may interact to influence long-term outcomes in WHF patients. This study evaluated the association between FGF23 levels and long-term outcomes in patients with WHF evaluated in the emergency department (ED). A total of 635 patients from the EAHFE registry, enrolled during 2007, 2009, and 2011, were prospectively included. FGF23 was measured in the first blood sample obtained at ED presentation. During a median follow-up of 380 days (interquartile range: 126 to 456), all-cause mortality occurred in 216 patients (34.0%), while 351 patients (55.3%) experienced the composite endpoint of death/WHF ED reconsultation and 295 (46.5%) experienced death/HF hospitalization. Event rates increased progressively across FGF23 levels. Patients with FGF23 above the median (48.4 pg/mL) displayed higher rates (per 100 patient-years) of all-cause mortality (49 vs. 31, <i>p</i> = 0.003), death/WHF ED reconsultation (93 vs. 65, <i>p</i> = 0.003), and death/HF hospitalization (77 vs. 56, <i>p</i> = 0.043). In continuous analyses, each doubling of FGF23 remained significantly associated with an increased risk of all three outcomes after multivariable adjustment. These associations were consistent across clinically relevant subgroups, including those defined by age, sex, and kidney function, supporting the potential prognostic value of FGF23 within this cohort, although external validation is warranted.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing YAP^WW1 and TAZ^WW: Similar Binding Sites but Different Stability and Conformational Dynamics.","authors":"Clara Merlen, Yannick Mesrouze, Suzanne Chau, Benjamin A Diehl, Alexandra Hinniger, Catherine Zimmermann, Marco Meyerhofer, Patrizia Fontana, Svenya Groebke, Jürgen Hinrichs, Wassim Abdul Rahman, Sascha Gutmann, César Fernández, Dušan Petrović, Patrick Chène","doi":"10.3390/biom16091355","DOIUrl":"10.3390/biom16091355","url":null,"abstract":"<p><p>The two paralogs YAP and TAZ act through TEAD transcription factors and bind PPxY motif proteins in the Hippo pathway via WW domains. YAP has up to two WW domains, whereas TAZ has one. Because YAP^WW1 and TAZ^WW are the most similar in sequence, they can be considered as corresponding modules in these two proteins. This study shows that, despite their similarity, they differ strongly in conformational stability and in how they bind flexible ligands. Nano-differential scanning fluorimetry, circular dichroism, and NMR indicate that both isolated domains populate partially folded or exchanging states in solution, but TAZ^WW is more thermally stable and has a larger folded population. Peptide binding stabilizes both domains, producing sharper NMR signals. Surface plasmon resonance measurements with PPxY peptides show micromolar affinities and generally modest differences between YAP^WW1 and TAZ^WW, although these differences increase for conformationally plastic ligands. A high resolution LATS2:YAP^WW1 crystal structure and molecular dynamics simulations suggest that preorganized peptides bind more tightly and less selectively, while flexible peptides incur larger binding penalties that dynamic YAP^WW1 compensates more effectively. These observations indicate that differences in WW-domain stability contribute to subtle YAP/TAZ binding preferences despite conserved binding surfaces and evolutionary relatedness between the paralogs.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}