Early stages of Parkin activation - A computational study

Catarina Carvalheda Dos Santos, Juan Bueren-Calabuig, Atul Kumar, Helen Walden, Andrei Pisliakov

Research output: Contribution to journalMeeting abstract

Abstract

Parkin is an E3-ubiquitin ligase involved in the regulation of mitophagy. Upon activation, it mediates the transfer of ubiquitin (Ub) from an ubiquitin-conjugating enzyme (E2) to specific substrate proteins, labelling those for degradation. Recent biochemical and structural data suggested that several factors are involved in Parkin activation. However, the available data cannot unambiguously explain the mutual effect of these factors or the detailed sequence of steps on the molecular scale. In this work, we use a combination of computational tools to examine the effect of: i) phosphorylation of Parkin, ii) removal of the UBL domain, iii) allosteric regulation by phosphoubiquitin (pUb), and iv) reported pathogenic mutations, on Parkin’s stability and activation mechanism. Our results suggest that i) phosphorylation alone is unlikely to promote the transition from the inactive to active conformation; ii) UBL removal might facilitate E2 binding, but its complete detachment from Parkin is rather improbable in a physiological context; iii) pUb binding stabilises the active conformation of Parkin likely priming the activation process; iv) mutations involving residues at the UBL/RING1 interface lead to structural rearrangements suggested to be involved in the activation mechanism.
Original languageEnglish
Article numberP-154
Pages (from-to)S155
Number of pages1
JournalEuropean Biophysics Journal
Volume46
Issue numberSuppl 1
Early online dateJun 2017
DOIs
Publication statusPublished - 2017
EventEuropean Biophysics Congress - Edinburgh, United Kingdom
Duration: 16 Jul 2017 → …

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    Carvalheda Dos Santos, C., Bueren-Calabuig, J., Kumar, A., Walden, H., & Pisliakov, A. (2017). Early stages of Parkin activation - A computational study. European Biophysics Journal, 46(Suppl 1), S155. [P-154]. https://doi.org/10.1007/s00249-017-1222-x