Myelin Basic Protein Attenuates Furin-Mediated Bri2 Cleavage and Postpones Its Membrane Trafficking

Autor: Evgeniya V. Smirnova, Vladimir I. Timofeev, Tatiana V. Rakitina, Dmitry E. Petrenko, Olga S. Elmeeva, George A. Saratov, Anna A. Kudriaeva, Eduard V. Bocharov, Alexey A. Belogurov
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 25, Iss 5, p 2608 (2024)
Druh dokumentu: article
ISSN: 25052608
1422-0067
1661-6596
DOI: 10.3390/ijms25052608
Popis: Myelin basic protein (MBP) is the second most abundant protein in the central nervous system and is responsible for structural maintenance of the myelin sheath covering axons. Previously, we showed that MBP has a more proactive role in the oligodendrocyte homeostasis, interacting with membrane-associated proteins, including integral membrane protein 2B (ITM2B or Bri2) that is associated with familial dementias. Here, we report that the molecular dynamics of the in silico-generated MBP-Bri2 complex revealed that MBP covers a significant portion of the Bri2 ectodomain, assumingly trapping the furin cleavage site, while the surface of the BRICHOS domain, which is responsible for the multimerization and activation of the Bri2 high-molecular-weight oligomer chaperone function, remains unmasked. These observations were supported by the co-expression of MBP with Bri2, its mature form, and disease-associated mutants, which showed that in mammalian cells, MBP indeed modulates the post-translational processing of Bri2 by restriction of the furin-catalyzed release of its C-terminal peptide. Moreover, we showed that the co-expression of MBP and Bri2 also leads to an altered cellular localization of Bri2, restricting its membrane trafficking independently of the MBP-mediated suppression of the Bri2 C-terminal peptide release. Further investigations should elucidate if these observations have physiological meaning in terms of Bri2 as a MBP chaperone activated by the MBP-dependent postponement of Bri2 membrane trafficking.
Databáze: Directory of Open Access Journals
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