TY - JOUR

T1 - Acidic sphingomyelinase interactions with lysosomal membranes and cation amphiphilic drugs

T2 - A molecular dynamics investigation

AU - Scrima, Simone

AU - Lambrughi, Matteo

AU - Favaro, Lorenzo

AU - Maeda, Kenji

AU - Jäättelä, Marja

AU - Papaleo, Elena

N1 - Publisher Copyright: © 2024

PY - 2024

Y1 - 2024

N2 - Lysosomes are pivotal in cellular functions and disease, influencing cancer progression and therapy resistance with Acid Sphingomyelinase (ASM) governing their membrane integrity. Moreover, cation amphiphilic drugs (CADs) are known as ASM inhibitors and have anti-cancer activity, but the structural mechanisms of their interactions with the lysosomal membrane and ASM are poorly explored. Our study, leveraging all-atom explicit solvent molecular dynamics simulations, delves into the interaction of glycosylated ASM with the lysosomal membrane and the effects of CAD representatives, i.e., ebastine, hydroxyebastine and loratadine, on the membrane and ASM. Our results confirm the ASM association to the membrane through the saposin domain, previously only shown with coarse-grained models. Furthermore, we elucidated the role of specific residues and ASM-induced membrane curvature in lipid recruitment and orientation. CADs also interfere with the association of ASM with the membrane at the level of a loop in the catalytic domain engaging in membrane interactions. Our computational approach, applicable to various CADs or membrane compositions, provides insights into ASM and CAD interaction with the membrane, offering a valuable tool for future studies.

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

KW - Acid sphingomyelinase

KW - Cation amphiphilic drugs

KW - Ebastine

KW - Loratadine

KW - Lysosomal membrane

KW - Molecular dynamics simulations

U2 - 10.1016/j.csbj.2024.05.049

DO - 10.1016/j.csbj.2024.05.049

M3 - Journal article

AN - SCOPUS:85195815088

VL - 23

SP - 2516

EP - 2533

JO - Computational and Structural Biotechnology Journal

JF - Computational and Structural Biotechnology Journal

SN - 2001-0370

ER -