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Analysis of the Ub to Ub-CR Transition in Ubiquitin.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Abstract

A new conformation has recently been reported for ubiquitin (Ub). This invisible conformation (Ub-CR), where the C-terminal tail is retracted, has a key functional role in phosphorylation of the Ser65 residue, a trigger for PINK1 and Parkin dependent mitophagy. Here we calculate the transition mechanism and associated rates for the Ub to Ub-CR pathway in the wild-type protein and a selection of mutants. We predict a cooperative one-step process with a transition state that resembles the Ub configuration, characterized by a loss of all interactions of the C-terminal tail with surrounding residues, and an open ubiquitin scaffold. The calculated observables agree well with reported values, and we make a range of predictions to guide future experiments. In particular, the effect of mutations on the pathway and the corresponding structural ensembles should have observable consequences. This feedback between theory and experiment promises new insight into key cellular processes.

Description

Keywords

Humans, Models, Molecular, Mutation, Protein Conformation, Ubiquitin, Ubiquitination

Journal Title

Biochemistry

Conference Name

Journal ISSN

0006-2960
1520-4995

Volume Title

57

Publisher

American Chemical Society (ACS)
Sponsorship
EPSRC (1652488)
Engineering and Physical Sciences Research Council (EP/N035003/1)
EPSRC