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Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide-Mcl1 Complexes.

ABSTRACT: Mcl1 is a primary member of the Bcl-2 family-anti-apoptotic proteins (AAP)-that is overexpressed in several cancer pathologies. The apoptotic regulation is mediated through the binding of pro-apoptotic peptides (PAPs) (e.g., Bak and Bid) at the canonical hydrophobic binding groove (CBG) of Mcl1. Although all PAPs form amphipathic ?-helices, their amino acid sequences vary to different degree. This sequence variation exhibits a central role in the binding partner selectivity towards different AAPs. Thus, constructing a novel peptide or small organic molecule with the ability to mimic the natural regulatory process of PAP is essential to inhibit various AAPs. Previously reported experimental binding free energies (BFEs) were utilized in the current investigation aimed to understand the mechanistic basis of different PAPs targeted to mMcl1. Molecular dynamics (MD) simulations used to estimate BFEs between mMcl1-PAP complexes using Molecular Mechanics-Generalized Born Solvent Accessible (MMGBSA) approach with multiple parameters. Predicted BFE values showed an excellent agreement with the experiment (R2 = 0.92). The van-der Waals (?Gvdw) and electrostatic (?Gele) energy terms found to be the main energy components that drive heterodimerization of mMcl1-PAP complexes. Finally, the dynamic network analysis predicted the allosteric signal transmission pathway involves more favorable energy contributing residues. In total, the results obtained from the current investigation may provide valuable insights for the synthesis of a novel peptide or small organic inhibitor targeting Mcl1.

SUBMITTER: Marimuthu P

PROVIDER: S-EPMC7463671 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide-Mcl1 Complexes.

Marimuthu Parthiban P Razzokov Jamoliddin J Singaravelu Kalaimathy K Bogaerts Annemie A

Biomolecules 20200728 8

Mcl1 is a primary member of the Bcl-2 family-anti-apoptotic proteins (AAP)-that is overexpressed in several cancer pathologies. The apoptotic regulation is mediated through the binding of pro-apoptotic peptides (PAPs) (e.g., Bak and Bid) at the canonical hydrophobic binding groove (CBG) of Mcl1. Although all PAPs form amphipathic α-helices, their amino acid sequences vary to different degree. This sequence variation exhibits a central role in the binding partner selectivity towards different AAP ...[more]

PMID: 32731448

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Project description:The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here, we show that oncogenic RAS and BRAF induce perinuclear relocalization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2? colocalizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSC) are present in tumor cell lines, mouse lung tumors, and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GF) in nontransformed cells with delayed kinetics (4-6 hours), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the prosenescence transcription factor C/EBP? in primary MEFs undergoing senescence. Conversely, in tumor cells, C/EBP? activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBP?.Significance: In addressing the long-standing question of the difference between normal and oncogenic RAS pathway signaling, this study shows that oncogenic RAS specifically triggers constitutive endocytosis-dependent movement of effector kinases to a perinuclear region, thereby creating connections to unique downstream targets such as the core prosenescence and the inflammatory regulatory transcription factor C/EBP?. Cancer Res; 78(4); 891-908. ©2017 AACR.

Dataset Information

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide-Mcl1 Complexes.

Publications

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide-Mcl1 Complexes.

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