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Updated: Jun 17, 2026
07:08
Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
Functionally compensating coevolving positions are neither homoplasic nor conserved in clades
Gregory B Gloor1, Gaurav Tyagi, Dana M Abrassart
1Department of Biochemistry, University of Western Ontario, London, Ontario, Canada. ggloor@uwo.ca
Molecular Biology and Evolution
|January 13, 2010
Summary
This study identifies non-conserved covarying positions in phosphoglycerate kinase that are crucial for protein function. These functionally important sites can be accurately identified even when residues vary, advancing protein engineering and evolutionary studies.
Area of Science:
- Biochemistry
- Molecular Biology
- Evolutionary Biology
Background:
- Covarying positions in proteins can indicate functional or structural relationships.
- Identifying such positions is challenging, especially when residues are not conserved.
Purpose of the Study:
- To investigate the functional significance of covarying positions in phosphoglycerate kinase.
- To determine if non-conserved covarying positions can be reliably identified.
Main Methods:
- Application of nonparametric covariation measures.
- Analysis of sequence diversity and clade conservation.
- Site-directed mutagenesis experiments.
Main Results:
- A specific pair of positions in phosphoglycerate kinase scored highly for covariation and were essential for function.
- Covarying positions were not explained by simple clade conservation or homoplasy.
- Mutagenesis revealed epistatic interactions between the identified covarying residues.
Conclusions:
- Non-conserved covarying positions that impact protein function can be precisely identified.
- This method offers a powerful tool for understanding protein evolution and engineering.
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