Understanding the origins of loss of protein function by analyzing the effects of thousands of variants on activity and abundance
Understanding the origins of loss of protein function by analyzing the effects of thousands of variants on activity and abundance
Abstract 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.
Valanciute Audrone、Hartmann-Petersen Rasmus、Lindorff-Larsen Kresten、Cagiada Matteo、Yang Jun J.、Stein Amelie、Fowler Douglas M.、Johansson Kristoffer E.、Nielsen Sofie V.
Linderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenDepartment of Pharmaceutical Sciences and Department of Oncology, St. Jude Children?ˉs Research HospitalLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenDepartment of Genome Sciences, University of Washington||Department of Bioengineering, University of Washington||Genetic Networks Program, CIFARLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of CopenhagenLinderstr?m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen
生物科学现状、生物科学发展生物科学研究方法、生物科学研究技术分子生物学生物化学
Valanciute Audrone,Hartmann-Petersen Rasmus,Lindorff-Larsen Kresten,Cagiada Matteo,Yang Jun J.,Stein Amelie,Fowler Douglas M.,Johansson Kristoffer E.,Nielsen Sofie V..Understanding the origins of loss of protein function by analyzing the effects of thousands of variants on activity and abundance[EB/OL].(2025-03-28)[2025-06-06].https://www.biorxiv.org/content/10.1101/2020.09.28.317040.点此复制
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