Acidic sphingomyelinase interactions with lysosomal membranes and cation amphiphilic drugs: A molecular dynamics investigation DOI Creative Commons
Simone Scrima, Matteo Lambrughi, Lorenzo Favaro

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 2516 - 2533

Published: June 2, 2024

Lysosomes are pivotal in cellular functions and disease, influencing cancer progression therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) known as ASM inhibitors have anti-cancer activity, but the structural mechanisms of interactions lysosomal poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into interaction glycosylated effects CAD representatives, i.e., ebastine, hydroxyebastine loratadine, on ASM. results confirm association to through saposin domain, previously only shown coarse-grained models. Furthermore, we elucidated role specific residues ASM-induced curvature lipid recruitment orientation. CADs also interfere at level a loop catalytic domain engaging interactions. computational approach, applicable various or compositions, provides insights membrane, offering valuable tool for future studies.

Language: Английский

Theoretical Study of Sphingomyelinases from Entamoeba histolytica and Trichomonas vaginalis Sheds Light on the Evolution of Enzymes Needed for Survival and Colonization DOI Creative Commons
Fátima Berenice Ramírez‐Montiel,

Sairy Andrade-Guillén,

Ana Laura Medina-Nieto

et al.

Pathogens, Journal Year: 2025, Volume and Issue: 14(1), P. 32 - 32

Published: Jan. 5, 2025

The path to survival for pathogenic organisms is not straightforward. Pathogens require a set of enzymes tissue damage generation and obtain nourishment, as well toolbox full alternatives bypass host defense mechanisms. Our group has shown that the parasitic protist Entamoeba histolytica encodes 14 sphingomyelinases (SMases); one them (acid sphingomyelinase 6, aSMase6) involved in repairing membrane exhibits hemolytic activity. enzymatic characterization aSMase6 been be activated by magnesium ions but zinc, human aSMase, strongly inhibited cobalt. However, no structural data are available enzyme. In this work, bioinformatic analyses showed aSMases diverse enzymes, evolutionarily related hemolysins derived from bacteria, similar overall structure parasitic, free-living protists mammalian enzymes. AlphaFold3 models predicted occupancy cobalt active site Cavity blind docking substrate pushed outward when bound instead ions. Additionally, E. loop absent rest aSMases, suggesting it may activity, demonstrated experimentally using recombinant proteins aSMase4 aSMase6. Trichomonas vaginalis show putative transmembrane domain seem functionally different histolytica. This work provides insight into future biochemical can mechanistic features sphingomyelinases, ultimately rendering these potential therapeutic targets.

Language: Английский

Citations

0
Predicting the structure-altering mechanisms of disease variants DOI Creative Commons

Matteo Arnaudi,

Mattia Utichi, Matteo Tiberti

et al.

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 91, P. 102994 - 102994

Published: Feb. 27, 2025

Missense variants can affect the severity of disease, choice treatment, and treatment outcomes. While number known has been increasing at a rapid pace, available evidence their clinical effect lagging behind, constituting challenge for clinicians researchers. Multiplexed assays variant effects (MAVEs) are important to close gap; nonetheless, computational predictions pathogenicity still often only data scoring variants. Such methods not designed provide mechanistic explanation amino acid substitutions. To this purpose, we propose structure-based frameworks as ensemble methodologies, with each method tailored predict different aspect among those exerted by substitutions link predicted indicators. We review frameworks, well advancements in underlying that on several protein features, such stability, biomolecular interactions, allostery, post-translational modifications, more.

Language: Английский

Citations

0
Acid sphingomyelinase deficiency: Laboratory diagnosis, genetic and epidemiologic aspects of a 50-year French cohort DOI

Roseline Froissart,

Magali Pettazzoni,

Cécile Pagan

et al.

Molecular Genetics and Metabolism, Journal Year: 2025, Volume and Issue: 145(1), P. 109081 - 109081

Published: March 11, 2025

Language: Английский

Citations

0
Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity DOI Creative Commons
Claudio Laquatra,

Albert M. Magro,

Federica Guarra

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 12, 2025

Abstract The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia cancer. Recent evidence indicated that mutations are involved several disorders, even though the structural basis for impact point on functions never been studied. By exploiting modular structure-based framework molecular dynamics simulations, we investigated effect five structure stability. Each mutation differentially impacts long-range interactions, intra inter-protomer ATPase activity. Changes these parameters influence functions, as revealed by their effects interactor succinate dehydrogenase (SDH). In keeping with this, affect growth migration aggressive sarcoma cells, alter sensitivity to selective inhibitor. Our work provides new insights structure-activity relationship TRAP1, identifying crucial amino acid residues regulate proteostatic pro-neoplastic

Language: Английский

Citations

0
MAVISp: A Modular Structure-Based Framework for Protein Variant Effects DOI Creative Commons

Matteo Arnaudi,

Ludovica Beltrame, Kristine Degn

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 24, 2022

The role of genomic variants in disease has expanded significantly with the advent advanced sequenc-ing techniques. rapid increase identified led to many being classi-fied as Variants Uncertain Significance or having conflicting evidence, posing challenges for their interpretation and characterization. Additionally, current methods predicting pathogenic often lack insights into underlying molecular mechanisms. Here, we introduce MAVISp (Multi-layered As-sessment VarIants by Structure proteins), a modular structural framework variant effects, ac-companied web server (https://services.healthtech.dtu.dk/services/MAVISp-1.0/) enhance data accessibility, consultation, re-usability. currently provides 700 proteins, encompassing over six million variants. A team biocurators regularly analyze update protein entries using standardized workflows, incorporating free energy calculations biomolecular simulations. We illustrate utility through selected case studies. facilitates analysis ef-fects at level potential advance understanding application mutational research.

Language: Английский

Citations

14
Acidic sphingomyelinase interactions with lysosomal membranes and cation amphiphilic drugs: A molecular dynamics investigation DOI Creative Commons
Simone Scrima, Matteo Lambrughi, Lorenzo Favaro

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 2516 - 2533

Published: June 2, 2024

Lysosomes are pivotal in cellular functions and disease, influencing cancer progression therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) known as ASM inhibitors have anti-cancer activity, but the structural mechanisms of interactions lysosomal poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into interaction glycosylated effects CAD representatives, i.e., ebastine, hydroxyebastine loratadine, on ASM. results confirm association to through saposin domain, previously only shown coarse-grained models. Furthermore, we elucidated role specific residues ASM-induced curvature lipid recruitment orientation. CADs also interfere at level a loop catalytic domain engaging interactions. computational approach, applicable various or compositions, provides insights membrane, offering valuable tool for future studies.

Language: Английский

Citations

0