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 → …

Fingerprint

Mitochondrial Degradation
Phosphorylation
Allosteric Regulation
Ubiquitin-Conjugating Enzymes
Mutation
Ubiquitin-Protein Ligases
Ubiquitin
Proteins

Cite this

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
Carvalheda Dos Santos, Catarina ; Bueren-Calabuig, Juan ; Kumar, Atul ; Walden, Helen ; Pisliakov, Andrei. / Early stages of Parkin activation - A computational study. In: European Biophysics Journal. 2017 ; Vol. 46, No. Suppl 1. pp. S155.
@article{152970a9501b4f7c84353d60a7ec2773,
title = "Early stages of Parkin activation - A computational study",
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.",
author = "{Carvalheda Dos Santos}, Catarina and Juan Bueren-Calabuig and Atul Kumar and Helen Walden and Andrei Pisliakov",
year = "2017",
doi = "10.1007/s00249-017-1222-x",
language = "English",
volume = "46",
pages = "S155",
journal = "European Biophysics Journal",
issn = "0175-7571",
publisher = "Springer Verlag",
number = "Suppl 1",

}

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, vol. 46, no. Suppl 1, P-154, pp. S155. https://doi.org/10.1007/s00249-017-1222-x

Early stages of Parkin activation - A computational study. / Carvalheda Dos Santos, Catarina; Bueren-Calabuig, Juan; Kumar, Atul; Walden, Helen; Pisliakov, Andrei.

In: European Biophysics Journal, Vol. 46, No. Suppl 1, P-154, 2017, p. S155.

Research output: Contribution to journalMeeting abstract

TY - JOUR

T1 - Early stages of Parkin activation - A computational study

AU - Carvalheda Dos Santos, Catarina

AU - Bueren-Calabuig, Juan

AU - Kumar, Atul

AU - Walden, Helen

AU - Pisliakov, Andrei

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1007/s00249-017-1222-x

DO - 10.1007/s00249-017-1222-x

M3 - Meeting abstract

VL - 46

SP - S155

JO - European Biophysics Journal

JF - European Biophysics Journal

SN - 0175-7571

IS - Suppl 1

M1 - P-154

ER -

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