A mutational atlas for Parkin proteostasis

Lene Clausen, Vasileios Voutsinos, Matteo Cagiada, Kristoffer E. Johansson, Martin Grønbæk-Thygesen, Snehal Nariya, Rachel L. Powell, Magnus K. N. Have, Vibe H. Oestergaard, Amelie Stein, Douglas M. Fowler (), Kresten Lindorff-Larsen () and Rasmus Hartmann-Petersen ()
Additional contact information
Lene Clausen: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Vasileios Voutsinos: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Matteo Cagiada: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Kristoffer E. Johansson: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Martin Grønbæk-Thygesen: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Snehal Nariya: University of Washington
Rachel L. Powell: University of Washington
Magnus K. N. Have: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Vibe H. Oestergaard: University of Copenhagen
Amelie Stein: University of Copenhagen
Douglas M. Fowler: University of Washington
Kresten Lindorff-Larsen: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
Rasmus Hartmann-Petersen: Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Proteostasis can be disturbed by mutations affecting folding and stability of the encoded protein. An example is the ubiquitin ligase Parkin, where gene variants result in autosomal recessive Parkinsonism. To uncover the pathological mechanism and provide comprehensive genotype-phenotype information, variant abundance by massively parallel sequencing (VAMP-seq) is leveraged to quantify the abundance of Parkin variants in cultured human cells. The resulting mutational map, covering 9219 out of the 9300 possible single-site amino acid substitutions and nonsense Parkin variants, shows that most low abundance variants are proteasome targets and are located within the structured domains of the protein. Half of the known disease-linked variants are found at low abundance. Systematic mapping of degradation signals (degrons) reveals an exposed degron region proximal to the so-called “activation element”. This work provides examples of how missense variants may cause degradation either via destabilization of the native protein, or by introducing local signals for degradation.

Date: 2024
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DOI: 10.1038/s41467-024-45829-4

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