Effect of fkbp12-derived intracellular peptides on rapamycin-induced fkbp-frb interaction and autophagy

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dc.creatorCarolina Angelica da Silva Parada
dc.creatorWilliam Tadeu Lara Festuccia
dc.creatorLuciano Borges Censoni
dc.creatorIvarne Luis dos Santos Tersariol
dc.creatorEmer Suavinho Ferro
dc.creatorIvan Pires de Oliveira
dc.creatorMayara Calegaro Ferrari Gewehr
dc.creatorJoão Agostinho Machado Neto
dc.creatorKeli Cristina de Lima
dc.creatorRosangela Aparecida dos Santos Eichler
dc.creatorLucia Rossetti Lopes
dc.creatorLuiz Roberto Grassmann Bechara
dc.creatorJulio Cesar Batista Ferreira
dc.date.accessioned2023-12-21T20:01:40Z
dc.date.accessioned2025-09-09T01:13:25Z
dc.date.available2023-12-21T20:01:40Z
dc.date.issued2022
dc.identifier.issn2073-4409
dc.identifier.urihttps://hdl.handle.net/1843/62125
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofCells
dc.rightsAcesso Aberto
dc.subjectPeptídeos
dc.subjectProteinas
dc.subjectProteina de ligação
dc.subject.otherIntracellular peptides
dc.subject.otherProtein–protein interaction
dc.subject.othermTORC1
dc.subject.otherEdgotype
dc.titleEffect of fkbp12-derived intracellular peptides on rapamycin-induced fkbp-frb interaction and autophagy
dc.typeArtigo de periódico
local.citation.issue3
local.citation.volume11
local.description.resumoIntracellular peptides (InPeps) generated by proteasomes were previously suggested as putative natural regulators of protein–protein interactions (PPI). Here, the main aim was to investigate the intracellular effects of intracellular peptide VFDVELL (VFD7) and related peptides on PPI. The internalization of the peptides was achieved using a C-terminus covalently bound cell-penetrating peptide (cpp; YGRKKRRQRRR). The possible inhibition of PPI was investigated using a NanoBiT® luciferase structural complementation reporter system, with a pair of plasmids vectors each encoding, simultaneously, either FK506-binding protein (FKBP) or FKBP-binding domain (FRB) of mechanistic target of rapamycin complex 1 (mTORC1). The interaction of FKBP–FRB within cells occurs under rapamycin induction. Results shown that rapamycin-induced interaction between FKBP–FRB within human embryonic kidney 293 (HEK293) cells was inhibited by VFD7-cpp (10–500 nM) and FDVEL- LYGRKKRRQRRR (VFD6-cpp; 1–500 nM); additional VFD7-cpp derivatives were either less or not effective in inhibiting FKBP–FRB interaction induced by rapamycin. Molecular dynamics simula- tions suggested that selected peptides, such as VFD7-cpp, VFD6-cpp, VFAVELLYGRKKKRRQRRR (VFA7-cpp), and VFEVELLYGRKKKRRQRRR (VFA7-cpp), bind to FKBP and to FRB protein surfaces. However, only VFD7-cpp and VFD6-cpp induced changes on FKBP structure, which could help with understanding their mechanism of PPI inhibition. InPeps extracted from HEK293 cells were found mainly associated with macromolecular components (i.e., proteins and/or nucleic acids), contributing to understanding InPeps’ intracellular proteolytic stability and mechanism of action-inhibiting PPI within cells. In a model of cell death induced by hypoxia-reoxygenation, VFD6-cpp (1 μM) increased the viability of mouse embryonic fibroblasts cells (MEF) expressing mTORC1-regulated autophagy-related gene 5 (Atg5), but not in autophagy-deficient MEF cells lacking the expression of Atg5. These data suggest that VFD6-cpp could have therapeutic applications reducing undesired side effects of rapamycin long-term treatments. In summary, the present report provides further evidence that In Peps have biological significance and could be valuable tools for the rational design of therapeutic molecules targeting intracellular PPI.
local.publisher.countryBrasil
local.publisher.departmentICA - INSTITUTO DE CIÊNCIAS AGRÁRIAS
local.publisher.initialsUFMG
local.url.externahttps://doi.org/10.3390/cells11030385

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