Interaction of the cryptic fragment of myelin basic protein with mitochondrial voltage-dependent anion-selective channel-1 affects cell energy metabolism
| Autor: | Albert G. Remacle, Piotr Cieplak, Jennifer Dolkas, Andrei V. Chernov, Veronica I. Shubayev, Mila Angert, Swathi K. Hullugundi, Alex Y. Strongin, David Scott |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell type Cell Mitochondrion Biochemistry Article Protein Structure Secondary Mice 03 medical and health sciences Myelin Adenosine Triphosphate Protein Domains Cell Line Tumor medicine Animals Humans Glycolysis Molecular Biology biology Chemistry Voltage-Dependent Anion Channel 1 Myelin Basic Protein Cell Biology Warburg effect Peptide Fragments Mitochondria Rats Cell biology Myelin basic protein 030104 developmental biology medicine.anatomical_structure Anaerobic glycolysis biology.protein Energy Metabolism |
| Zdroj: | Biochemical Journal. 475:2355-2376 |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | In demyelinating nervous system disorders, myelin basic protein (MBP), a major component of the myelin sheath, is proteolyzed and its fragments are released in the neural environment. Here, we demonstrated that, in contrast with MBP, the cellular uptake of the cryptic 84–104 epitope (MBP84-104) did not involve the low-density lipoprotein receptor-related protein-1, a scavenger receptor. Our pull-down assay, mass spectrometry and molecular modeling studies suggested that, similar with many other unfolded and aberrant proteins and peptides, the internalized MBP84-104 was capable of binding to the voltage-dependent anion-selective channel-1 (VDAC-1), a mitochondrial porin. Molecular modeling suggested that MBP84-104 directly binds to the N-terminal α-helix located midway inside the 19 β-blade barrel of VDAC-1. These interactions may have affected the mitochondrial functions and energy metabolism in multiple cell types. Notably, MBP84-104 caused neither cell apoptosis nor affected the total cellular ATP levels, but repressed the aerobic glycolysis (lactic acid fermentation) and decreased the l-lactate/d-glucose ratio (also termed as the Warburg effect) in normal and cancer cells. Overall, our findings implied that because of its interactions with VDAC-1, the cryptic MBP84-104 peptide invoked reprogramming of the cellular energy metabolism that favored enhanced cellular activity, rather than apoptotic cell death. We concluded that the released MBP84-104 peptide, internalized by the cells, contributes to the reprogramming of the energy-generating pathways in multiple cell types. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|