Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
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Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants. / Grønbæk-Thygesen, Martin; Voutsinos, Vasileios; Johansson, Kristoffer E.; Schulze, Thea K.; Cagiada, Matteo; Pedersen, Line; Clausen, Lene; Nariya, Snehal; Powell, Rachel L.; Stein, Amelie; Fowler, Douglas M.; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.
In: Nature Communications, Vol. 15, No. 1, 4026, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
AU - Grønbæk-Thygesen, Martin
AU - Voutsinos, Vasileios
AU - Johansson, Kristoffer E.
AU - Schulze, Thea K.
AU - Cagiada, Matteo
AU - Pedersen, Line
AU - Clausen, Lene
AU - Nariya, Snehal
AU - Powell, Rachel L.
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 - Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 (~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.
AB - Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 (~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.
U2 - 10.1038/s41467-024-48481-0
DO - 10.1038/s41467-024-48481-0
M3 - Journal article
C2 - 38740822
AN - SCOPUS:85192871645
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4026
ER -
ID: 392567884