Comprehensive analysis of all evolutionary paths between two divergent PDZ domain specificities
Joan Teyra1, Andreas Ernst2, Alex Singer1
1The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
Protein Science : a Publication of the Protein Society
|October 27, 2019
Summary
Small genetic changes can significantly alter protein specificity, driving functional diversity. This study reveals how minimal mutations in peptide-binding domains lead to novel functions, supporting evolutionary models of protein adaptation.
Area of Science:
- Molecular Biology
- Protein Engineering
- Evolutionary Biology
Background:
- Protein functional diversity arises from molecular evolution.
- PDZ domains are crucial for protein-protein interactions.
- Understanding specificity transitions is key to protein evolution.
Purpose of the Study:
- Investigate the impact of all mutation combinations on protein specificity.
- Map the evolutionary pathways between divergent peptide-binding domains.
- Elucidate the structural basis of specificity transitions.
Main Methods:
- Constructed a panel of 64 PDZ domain variants covering all mutation combinations.
- Assessed specificity profiles using a comprehensive heptapeptide library.
- Determined structural basis via X-ray crystallography.
Main Results:
- Specificity profiles clustered into six distinct groups, indicating evolutionary nodes.
- Three substitutions were sufficient to switch specificity from Erbin-PDZ to Pdlim4-PDZ.
- A single binding site substitution, supported by others, altered ligand conformation.
Conclusions:
- Minimal mutations can dramatically alter protein specificity and function.
- Intermediate protein variants can serve as crucial evolutionary intermediates.
- Findings support gene duplication and cumulative mutation models for evolving complex protein functions.
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