Molecular principles underlying aggressive cancers

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 16, 2025

Language: Английский

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Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss‐of‐function and gain‐of‐function mutants

Protein Science, Journal Year: 2025, Volume and Issue: 34(2)

Published: Jan. 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.

Language: Английский

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Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome

npj Genomic Medicine, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 4, 2023

Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery cancer in afflicted NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias numbers. As NDD-associated mutations, most cases, they germline while mutations sporadic, emerging during life. However, somatic mosaicism spur cancer-related germline. NDDs share proteins, pathways, mutations. Here we ask (i) exactly features share, (ii) how, despite their commonalities, differ clinical outcomes. To tackle these questions, employed a statistical framework followed network analysis. Our thorough exploration reconstructed disease-specific networks, transcriptome levels profiles autism spectrum disorder (ASD) cancers, point signaling strength key factor: strong promotes cell proliferation cancer, weaker (moderate) impacts differentiation ASD. Thus, strength, not activating decide outcome.

Language: Английский

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Mitogen signaling strength and duration can control cell cycle decisions

Science Advances, Journal Year: 2024, Volume and Issue: 10(27)

Published: July 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.

Language: Английский

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Slower CDK4 and faster CDK2 activation in the cell cycle

Structure, Journal Year: 2024, Volume and Issue: 32(8), P. 1269 - 1280.e2

Published: May 3, 2024

Language: Английский

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Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102279 - 102279

Published: March 22, 2024

Language: Английский

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Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(3), P. 862 - 873

Published: Jan. 12, 2024

The Ras homologue family member A (RhoA) is a of the Rho family, subgroup superfamily. RhoA interacts with 115 kDa guanine nucleotide exchange factor (p115-RhoGEF), which assists in activation and binding downstream effectors. Here, we use molecular dynamics (MD) simulations essential analysis inactive RhoA–GDP active RhoA–GTP, when bound to p115-RhoGEF decipher mechanism at structural level. We observe that maintains its position near catalytic site on Dbl homology (DH) domain through interaction Switch I region DH domain. further show RhoA–GTP engaged more interactions membrane-bound Pleckstrin (PH) as compared RhoA–GDP. hypothesize role between PH help release it from upon activation. Our results support this premise, our uncover beginning process provide details. They also point allosteric communication pathways take part promote strengthen Allosteric regulation occurs among other members Collectively, suggest process, after activation, making available

Language: Английский

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Review: Cancer and neurodevelopmental disorders: multi-scale reasoning and computational guide

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 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.

Language: Английский

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Cell phenotypes can be predicted from propensities of protein conformations

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 83, P. 102722 - 102722

Published: Oct. 21, 2023

Proteins exist as dynamic conformational ensembles. Here we suggest that the propensities of conformations can be predictors cell function. The states molecules preferentially visit viewed phenotypic determinants, and their mutations work by altering relative propensities, thus phenotype. Our examples include (i) inactive state variants harboring cancer driver present active state-like features, in K-Ras4B

Language: Английский

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SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities

Cellular and Molecular Life Sciences, Journal Year: 2023, Volume and Issue: 81(1)

Published: Dec. 12, 2023

Language: Английский

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