A mutational atlas for Parkin proteostasis

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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.
OriginalsprogEngelsk
Artikelnummer1541
TidsskriftNature Communications
Vol/bind15
Udgave nummer1
Antal sider17
ISSN2041-1723
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We acknowledge the use of the FACS and computing core facilities at the Biotech Research & Innovation Centre and Department of Biology, University of Copenhagen. We thank Michael Lisby, Søren Lindemose and Anne-Marie Lauridsen for assistance. We thank Nicholas A. Popp for assistance with the cloning strategy and methods. The allosteric Parkin modulator was kindly provided by Dr. Laura F. Silvian from Biogen.The present work was funded by the Novo Nordisk Foundation (https:// novonordiskfonden.dk) challenge program PRISM (to K.L.-L., A.S., D.M.F. & R.H.-P.), the Lundbeck Foundation ( https://www.lundbeckfonden.com ) R272-2017-452 and R209-2015-3283 (to A.S.) and R249-2017-510 (to L.C.), and Danish Council for Independent Research (Det Frie Forskningsråd) ( https://dff.dk ) 10.46540/2032-00007B (to R.H.P.).

Funding Information:
We acknowledge the use of the FACS and computing core facilities at the Biotech Research & Innovation Centre and Department of Biology, University of Copenhagen. We thank Michael Lisby, Søren Lindemose and Anne-Marie Lauridsen for assistance. We thank Nicholas A. Popp for assistance with the cloning strategy and methods. The allosteric Parkin modulator was kindly provided by Dr. Laura F. Silvian from Biogen.The present work was funded by the Novo Nordisk Foundation (https:// novonordiskfonden.dk) challenge program PRISM (to K.L.-L., A.S., D.M.F. & R.H.-P.), the Lundbeck Foundation (https://www.lundbeckfonden.com) R272-2017-452 and R209-2015-3283 (to A.S.) and R249-2017-510 (to L.C.), and Danish Council for Independent Research (Det Frie Forskningsråd) (https://dff.dk) 10.46540/2032-00007B (to R.H.P.).

Publisher Copyright:
© The Author(s) 2024.

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