Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance
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Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance. / Cagiada, Matteo; Johansson, Kristoffer E.; Valanciute, Audrone; Nielsen, Sofie V.; Hartmann-Petersen, Rasmus; Yang, Jun J.; Fowler, Douglas M.; Stein, Amelie; Lindorff-Larsen, Kresten.
In: Molecular Biology and Evolution, Vol. 38, No. 8, 2021, p. 3235-3246.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance
AU - Cagiada, Matteo
AU - Johansson, Kristoffer E.
AU - Valanciute, Audrone
AU - Nielsen, Sofie V.
AU - Hartmann-Petersen, Rasmus
AU - Yang, Jun J.
AU - Fowler, Douglas M.
AU - Stein, Amelie
AU - Lindorff-Larsen, Kresten
N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
PY - 2021
Y1 - 2021
N2 - Understanding and predicting how amino acid substitutions affect proteins is key to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analysed 6749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects, and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyse the structural and mechanistic origins of loss of function, and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance. In this way, our results link thermodynamic stability and evolutionary conservation to experimental studies of different properties of protein fitness landscapes.
AB - Understanding and predicting how amino acid substitutions affect proteins is key to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analysed 6749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects, and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyse the structural and mechanistic origins of loss of function, and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance. In this way, our results link thermodynamic stability and evolutionary conservation to experimental studies of different properties of protein fitness landscapes.
U2 - 10.1093/molbev/msab095
DO - 10.1093/molbev/msab095
M3 - Journal article
C2 - 33779753
VL - 38
SP - 3235
EP - 3246
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 8
ER -
ID: 261213249