The Parkin Protein and Disease Mutations

From the MRC Laboratory of Molecular Biology in the United Kingdom comes research that has determined the crystal structure of Parkin, a protein linked to Parkinson’s disease.  Results published in The EMBO Journal better define the positioning of many mutations that are linked to hereditary Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disease that occurs mostly in older individuals sporadically, or not hereditarily.  However, around 15% of patients develop symptoms early in life due to inherited mutations in a limited number of disease genes. These mutations are especially detrimental, causing more damage to nerve cells than non-mutated forms of Parkin.  Scientists believe this occurs because previous research has suggested the Parkin protein regulates energy production within cells.  For familial cases of inherited disease genes, around 50% are caused by mutations in the PARKIN gene that encodes a protein within the RBR ubiquitin ligase enzyme family. These mutated enzymes couple other proteins together within the cell to create a molecule called ubiquitin.  But since the enzymes catalyzing these reactions are mutated forms of the PARKIN gene, the critical ubiquitin proteins can be unstable or altered in their function.

EMBO investigator David Komander and his co-worker Tobias Wauer crystallized a form of human Parkin and used X-ray diffraction patterns to determine the way in which the protein chain folds into a three-dimensional structure. The experiments revealed the existence of an in-built control mechanism for Parkin activity, one that is lost in the presence of the mutations which cause Parkinson’s disease. Komander and Wauer pinpointed amino acids of Parkin that had key functions of ubiquitin ligase enzyme activity, and found that the proteins they create are sensitive to blocking by reagents that had already been categorized by their laboratory.  This means that after identifying building blocks of Parkin, the scientists blocked their ability to form larger, mutated, ubiquitin molecules.  The crystal structure of Parkin goes on to reveal secrets regarding the molecule, which scientists are hopeful may one day be used as a way to treat or slow the progression of Parkinson’s. There is reason to believe that other studies on crystal structure could lead scientists to find compounds that are capable of altering Parkin’s activity.

1) Tobias Wauer, David Komander. Structure of the human Parkin ligase domain in an autoinhibited state. The EMBO Journal, 2013; DOI: 10.1038/emboj.2013.125

2) EMBO – ecellence in life sciences (2013, May 31). How disease mutations affect the Parkin

protein. ScienceDaily. Retrieved June 3, 2013, from

By: Lauren Horne

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