Structural interface between LRRK2 and 14-3-3 protein

Loes M Stevers; Rens M J M de Vries; Richard G Doveston; Lech-Gustav Milroy; Luc Brunsveld; Christian Ottmann

doi:10.1042/BCJ20161078

Structural interface between LRRK2 and 14-3-3 protein

Biochem J. 2017 Mar 23;474(7):1273-1287. doi: 10.1042/BCJ20161078.

Authors

Loes M Stevers¹, Rens M J M de Vries¹, Richard G Doveston¹, Lech-Gustav Milroy¹, Luc Brunsveld¹, Christian Ottmann^{2

3}

Affiliations

¹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands.
² Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands [email protected].
³ Department of Chemistry, University of Duisburg-Essen, 45141 Essen, Germany.

PMID: 28202711
DOI: 10.1042/BCJ20161078

Abstract

Binding of 14-3-3 proteins to leucine-rich repeat protein kinase 2 (LRRK2) is known to be impaired by many Parkinson's disease (PD)-relevant mutations. Abrogation of this interaction is connected to enhanced LRRK2 kinase activity, which in turn is implicated in increased ubiquitination of LRRK2, accumulation of LRRK2 into inclusion bodies and reduction in neurite length. Hence, the interaction between 14-3-3 and LRRK2 is of significant interest as a possible drug target for the treatment of PD. However, LRRK2 possesses multiple sites that, upon phosphorylation, can bind to 14-3-3, thus rendering the interaction relatively complex. Using biochemical assays and crystal structures, we characterize the multivalent interaction between these two proteins.

Keywords: Parkinson's disease; crystallography; protein–protein interactions.

MeSH terms

14-3-3 Proteins / chemistry*
14-3-3 Proteins / genetics
14-3-3 Proteins / metabolism
Amino Acid Sequence
Binding Sites
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli / genetics
Escherichia coli / metabolism
Gene Expression
Humans
Kinetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / chemistry*
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
Models, Molecular
Mutation
Peptides / chemical synthesis
Peptides / chemistry*
Peptides / metabolism
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Recombinant Fusion Proteins / chemistry*
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid

Substances

14-3-3 Proteins
Peptides
Recombinant Fusion Proteins
YWHAZ protein, human
LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2