| Autor: |
Martin, Tyler A., Wu, Tiffany, Tang, Qingling, Dougherty, Larissa L., Parente, Daniel J, Swint-Kruse, Liskin, Fenton, Aron W. |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| DOI: |
10.1101/632562 |
| Popis: |
In the goal of interpreting human exomes, when predictive programs assign functional importance to some positions, they implicitly assume the existence of non-important positions – those that accommodate many side chain chemistries without altering function (“neutral”). However, very few (if any) experimental studies have demonstrated the existence of neutral positions. We sought experimental evidence for neutral positions using human liver pyruvate kinase (hLPYK) as a model system. To that end, we used multiple evolutionary criteria to identify 20 possibly neutral positions. Nine positions were further tested with a total of 117 amino acid substitutions. Although “all” potential hLPYK functions can never be explored, we measured effects on 5 parameters associated with substrate/ligand affinities and allosteric coupling. At each position, the aggregate outcomes of multiple variants were used to quantify “neutrality” scores. Three of the nine positions showed perfect neutral scores in all 5 parameters; a fourth position had high neutral scores. Although our strategy for predicting positions had low predictive power for the identification of neutral positions, all positions had neutral scores that were much higher than positions in functional sites. Given this evidence for the existence of neutral positions, similar studies should be carried out for other proteins to generate a database of well characterized neutral positions that can then be available to benchmark and validate predictions about amino acid substitutions. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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