A mutational atlas for Parkin proteostasis
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A mutational atlas for Parkin proteostasis. / Clausen, Lene; Voutsinos, Vasileios; Cagiada, Matteo; Johansson, Kristoffer E.; Grønbæk-Thygesen, Martin; Nariya, Snehal; Powell, Rachel L.; Have, Magnus K.N.; Oestergaard, Vibe H.; Stein, Amelie; Fowler, Douglas M.; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.
I: Nature Communications, Bind 15, Nr. 1, 1541, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A mutational atlas for Parkin proteostasis
AU - Clausen, Lene
AU - Voutsinos, Vasileios
AU - Cagiada, Matteo
AU - Johansson, Kristoffer E.
AU - Grønbæk-Thygesen, Martin
AU - Nariya, Snehal
AU - Powell, Rachel L.
AU - Have, Magnus K.N.
AU - Oestergaard, Vibe H.
AU - Stein, Amelie
AU - Fowler, Douglas M.
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-45829-4
DO - 10.1038/s41467-024-45829-4
M3 - Journal article
C2 - 38378758
AN - SCOPUS:85185529267
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1541
ER -
ID: 384493230