Опубликована: Янв. 1, 2024
Язык: Английский
Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)
Опубликована: Фев. 16, 2025
Язык: Английский
Процитировано
3
Science Advances, Год журнала: 2024, Номер 10(27)
Опубликована: Июль 5, 2024
Decades ago, mitogen-promoted signaling duration and strength were observed to be sensed by the cell critical for its decisions: proliferate or differentiate. Landmark publications established importance of mitogen not only in G 1 cycle phase but also through S 2 /M transition. Despite these early milestones, how signal strength, short strong weaker sustained, control fate has been largely unheeded. Here, we center on cardinal signaling-related questions, including (i) fluctuating mitogenic signals are converted into proliferation-differentiation decisions (ii) why extended weak is associated with differentiation, while bursts induce proliferation but, if too long, irreversible senescence. Our innovative broad outlook harnesses biology protein conformational ensembles, helping us define clarify decisions, thus fate.
Язык: Английский
Процитировано
14
Protein Science, Год журнала: 2025, Номер 34(2)
Опубликована: Янв. 22, 2025
Abstract Neurofibromin (NF1), a Ras GTPase‐activating protein (GAP), catalyzes Ras‐mediated GTP hydrolysis and thereby negatively regulates the Ras/MAPK pathway. NF1 mutations can cause neurofibromatosis type 1 manifesting tumors, neurodevelopmental disorders. Exactly how missense in GAP‐related domain of (NF1 GRD ) allosterically impact GAP to promote these distinct pathologies is unclear. Especially tantalizing question same‐domain, same‐residue variants exhibit clinical phenotypes. Guided by data, we take up this dilemma. We sampled conformational ensembles complex with GTP‐bound K‐Ras4B performing molecular dynamics simulations. Our results show that retain active conformation but biased propensities catalytically competent populations K‐Ras4B–NF1 complex. In agreement depiction experimental tagging, compared wild type, E1356A E1356V mutants effectively act through loss‐of‐function gain‐of‐function mechanisms, leading developmental disorders, respectively. Allosteric modulation activity biasing different states further demonstrated diminished isoform 2, as powerful predictors function. Taken together, our work identifies hotspot could tune function, suggests targeting oncogenic restoring catalytic activity, offers mechanism for phenotypes determined their propensities.
Язык: Английский
Процитировано
2
Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12
Опубликована: Июль 2, 2024
The connection and causality between cancer neurodevelopmental disorders have been puzzling. How can the same cellular pathways, proteins, mutations lead to pathologies with vastly different clinical presentations? And why do individuals disorders, such as autism schizophrenia, face higher chances of emerging throughout their lifetime? Our broad review emphasizes multi-scale aspect this type reasoning. As these examples demonstrate, rather than focusing on a specific organ system or disease, we aim at new understanding that be gained. Within framework, our calls attention computational strategies which powerful in discovering connections, causalities, predicting outcomes, are vital for drug discovery. Thus, centering features, draw rapidly increasing data molecular level, including mutations, isoforms, three-dimensional structures, expression levels respective disease-associated genes. Their integrated analysis, together chromatin states, delineate how, despite being connected, differ, how symptoms. Here, seek uncover cancer, pediatric tumors, tantalizing questions raises.
Язык: Английский
Процитировано
9
Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown
Опубликована: Янв. 10, 2025
mTOR plays a crucial role in PI3K/AKT/mTOR signaling. We hypothesized that activation mechanisms driving oncogenesis can advise effective therapeutic designs. To test this, we combined cancer genomic analysis with extensive molecular dynamics simulations of oncogenic variants. observed conformational changes within kinase domain are associated multiple mutational events. The mutations disturb the α-packing formed by kαAL, kα3, kα9, kα9b, and kα10 helices domain, creating cryptic pocket. Its opening correlates catalytic cleft, including active site residues realignment, favoring catalysis. pocket created disrupted coincides allosteric PI3Kα be harmoniously fitted inhibitor RLY-2608, suggesting analogous drugs designed based on RLY-2608 restore packed α-structure, resulting inactive conformation. Our results exemplify knowledge detailed inform innovative development.
Язык: Английский
Процитировано
1
Current Opinion in Structural Biology, Год журнала: 2025, Номер 91, С. 103000 - 103000
Опубликована: Фев. 8, 2025
Язык: Английский
Процитировано
1
Chemical Science, Год журнала: 2023, Номер 15(3), С. 1003 - 1017
Опубликована: Дек. 7, 2023
Inactive mTOR adopts a closed catalytic cleft with the spacing between allosteric and orthosteric sites creating favorable environment for bitopic inhibitors. Active features an open greater separation, rendering it less selective.
Язык: Английский
Процитировано
14
Neurobiology of Disease, Год журнала: 2024, Номер 199, С. 106597 - 106597
Опубликована: Июль 9, 2024
Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, networks. They also germline mutations an impaired prenatal differentiation origin. may differ in the timing of events proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to cell states, which depend on spatial location, gene expression during development. These attributes are crucial as develops sequentially, single-cell organization influences state, thus function. Our underlying premise is root cause pediatric differentiation. Data related tumors, disorders, (sub)types, locations, developing scant. However, emerging single technologies, including transcriptomic, biology, high-resolution imaging performed over developmental time, could be transformational deciphering pathologies thereby pharmacology.
Язык: Английский
Процитировано
5
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 21, 2025
ABSTRACT Missense mutations in oncogenic proteins that are concurrently associated with neurodevelopmental disorders have garnered significant attention. Phosphatase and tensin homolog (PTEN) serves as a paradigmatic model for mapping its mutational landscape identifying genotypic predictors of distinct phenotypic outcomes, including cancer autism spectrum disorder (ASD). Despite extensive research into the genotype-phenotype correlations PTEN mutations, mechanisms underlying dual association specific both ASD (PTEN-cancer/ASD mutations) remain elusive. This study introduces an integrative approach combines machine learning (ML) structural dynamics to elucidate molecular effects PTEN-cancer/ASD mutations. Analysis biophysical network biology-based signatures reveals complex energetic functional landscape. Subsequently, ML corresponding integrated score were developed classify predict underscoring significance protein predicting cellular phenotypes. Further simulations demonstrated induce dynamic alterations characterized by open conformational changes restricted P loop coupled inter-domain allosteric regulation. aims enhance understanding through interpretable analysis. By shared between ASD, findings pave way development novel therapeutic strategies.
Язык: Английский
Процитировано
0
Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169044 - 169044
Опубликована: Фев. 1, 2025
Язык: Английский
Процитировано
0