Heat shock protein (Hsp27)-ceramide synthase (Cers1) protein-protein interactions provide a new avenue for unexplored anti-cancer mechanism and therapy.

Ali, Musab; Zhang, Zhichao; Ibrahim, Mahmoud A A; Soliman, Mahmoud E S

Ali, Musab; Zhang, Zhichao; Ibrahim, Mahmoud A A; Soliman, Mahmoud E S.

Afiliación

Ali M; Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Durban, South Africa.
Zhang Z; School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China.
Ibrahim MAA; Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Durban, South Africa.
Soliman MES; Computational Chemistry Laboratory, Chemistry Department, Minia University, Minia, Egypt.

J Recept Signal Transduct Res ; : 1-13, 2024 Aug 27.

Article en En | MEDLINE | ID: mdl-39189140

ABSTRACT

ABSTRACT

Hsp27 is a member of the small heat-shock proteins (sHSPs) - the known cellular line of defence against abnormal protein folding behaviors. Nevertheless, its upregulation is linked to a variety of pathological disorders, including several types of cancers. The ceramide synthases (CerS) mediate the synthesis of ceramide, a critical structural and signaling lipid. Functionally, downstream ceramide metabolites are implicated in the apoptosis process and their abnormal functionality has been linked to anticancer resistance. Studies showed that CerS1 are possibly inhibited by Hsp27 leading to biochemical anticancer effects in vitro. Nevertheless, the nature of such protein-protein interaction (PPI) has not been considerably investigated in molecular terms, hence, we present the first description of the dynamics CerS1-Hsp27 interaction landscapes using molecular dynamics simulations. Time-scale molecular dynamics simulation analysis indicated a system-wide conformational events of decreased stability, increased flexibility, reduced compactness, and decreased folding of CerS1. Analysis of binding energy showed a favorable interaction entailing 56 residues at the interface and a total stabilizing energy of -158 KJ/mol. The CerS1 catalytic domain experienced an opposite trend compared to the protein backbone. Yet, these residues adopted a highly compact conformation as per DCCM and DSSP analysis. Furthermore, conserved residues (SER 212, ASP 213, ALA 240, GLY 243, ASP 319) comprising the substrate shuttling machinery showed notable rigidity implying a restrained ceramide precursor access and assembly; hence, a possible inhibitory mechanism. Findings from this report would streamline a better molecular understanding of CerS1-Hsp27 interactions and decipher its potential avenue toward unexplored anti-cancer mechanisms and therapy.

Palabras clave

Heat-shock proteins; anticancer agents; ceramide synthases; molecular chaperones; molecular dynamic simulation; protein-protein interactions

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Recept Signal Transduct Res Asunto de la revista: BIOQUIMICA / FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Sudáfrica Pais de publicación: Reino Unido

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