Coevolution-based inference of amino acid interactions underlying protein function
Protein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enab...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/34300 |
| _version_ | 1828107614370660352 |
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| author | Victor H Salinas Rama Ranganathan |
| author_facet | Victor H Salinas Rama Ranganathan |
| author_sort | Victor H Salinas |
| collection | DOAJ |
| description | Protein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in several homologs of a protein family – a deep coupling scan (DCS). The data show that cooperative interactions between residues are loaded in a sparse, evolutionarily conserved, spatially contiguous network of amino acids. The pattern of amino acid coupling is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work exposes the collective nature of physical constraints on protein function and clarifies its link with sequence analysis, enabling a general practical approach for understanding the structural basis for protein function. |
| first_indexed | 2024-04-11T10:34:56Z |
| format | Article |
| id | doaj.art-c9ee0da005a9432e9ff318e9ea0a3c46 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:34:56Z |
| publishDate | 2018-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c9ee0da005a9432e9ff318e9ea0a3c462022-12-22T04:29:20ZengeLife Sciences Publications LtdeLife2050-084X2018-07-01710.7554/eLife.34300Coevolution-based inference of amino acid interactions underlying protein functionVictor H Salinas0Rama Ranganathan1https://orcid.org/0000-0001-5463-8956Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, United StatesCenter for Physics of Evolving Systems, Biochemistry and Molecular Biology, The University of Chicago, Chicago, United States; Institute for Molecular Engineering, The University of Chicago, Chicago, United StatesProtein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in several homologs of a protein family – a deep coupling scan (DCS). The data show that cooperative interactions between residues are loaded in a sparse, evolutionarily conserved, spatially contiguous network of amino acids. The pattern of amino acid coupling is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work exposes the collective nature of physical constraints on protein function and clarifies its link with sequence analysis, enabling a general practical approach for understanding the structural basis for protein function.https://elifesciences.org/articles/34300cooperativityepistasisbindingevolutionmutagenesiscoevolution |
| spellingShingle | Victor H Salinas Rama Ranganathan Coevolution-based inference of amino acid interactions underlying protein function eLife cooperativity epistasis binding evolution mutagenesis coevolution |
| title | Coevolution-based inference of amino acid interactions underlying protein function |
| title_full | Coevolution-based inference of amino acid interactions underlying protein function |
| title_fullStr | Coevolution-based inference of amino acid interactions underlying protein function |
| title_full_unstemmed | Coevolution-based inference of amino acid interactions underlying protein function |
| title_short | Coevolution-based inference of amino acid interactions underlying protein function |
| title_sort | coevolution based inference of amino acid interactions underlying protein function |
| topic | cooperativity epistasis binding evolution mutagenesis coevolution |
| url | https://elifesciences.org/articles/34300 |
| work_keys_str_mv | AT victorhsalinas coevolutionbasedinferenceofaminoacidinteractionsunderlyingproteinfunction AT ramaranganathan coevolutionbasedinferenceofaminoacidinteractionsunderlyingproteinfunction |