Inactivation of Parkin by Oxidative Stress and C-terminal Truncations

  • Winklhofer K
  • Henn I
  • Kay-Jackson P
  • et al.
N/ACitations
Citations of this article
5Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Loss of parkin function is linked to autosomal recessive juvenile parkinsonism. Here we show that proteotoxic stress and short C-terminal truncations induce misfolding of parkin. As a consequence, wild-type parkin was depleted from a high molecular weight complex and inactivated by aggregation. Similarly, the pathogenic parkin mutant W453Stop, characterized by a C-terminal deletion of 13 amino acids, spontaneously adopted a misfolded conformation. Mutational analysis indicated that C-terminal truncations exceeding 3 amino acids abolished formation of detergent-soluble parkin. In the cytosol scattered aggregates of misfolded parkin contained the molecular chaperone Hsp70. Moreover, increased expression of chaperones prevented aggregation of wild-type parkin and promoted folding of the W453Stop mutant. Analyzing parkin folding in vitro indicated that parkin is aggregation-prone and that its folding is dependent on chaperones. Our study demonstrates that C-terminal truncations impede parkin folding and reveal a new mechanism for inactivation of parkin.

Cite

CITATION STYLE

APA

Winklhofer, K. F., Henn, I. H., Kay-Jackson, P. C., Heller, U., & Tatzelt, J. (2003). Inactivation of Parkin by Oxidative Stress and C-terminal Truncations. Journal of Biological Chemistry, 278(47), 47199–47208. https://doi.org/10.1074/jbc.m306769200

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free