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Related Experiment Video

Updated: Nov 19, 2025

Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues

Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues

Published on: July 14, 2015

Were Ancestral Proteins Less Specific?

Lucas C Wheeler^1,2,3, Michael J Harms^1,2

¹Institute of Molecular Biology, University of Oregon, Eugene, OR, USA.

Molecular Biology and Evolution

|February 2, 2021

Summary

This summary is machine-generated.

Ancestral proteins may not be less specific than modern ones. This study suggests that using biological targets to infer protein evolution trends from ancestral proteins may be misleading.

Keywords:

S100 ancestral sequence reconstruction phage display phylogenetics protein evolution specificity

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Area of Science:

Biochemistry
Evolutionary Biology
Protein Engineering

Background:

The hypothesis that ancestral proteins were less specific than modern proteins is debated.
Ancestral sequence reconstruction is used to study protein evolution.
Previous studies suggested S100A5 and S100A6 evolved increased specificity.

Purpose of the Study:

To re-evaluate the specificity of ancestral proteins compared to their descendants.
To investigate the evolution of peptide-binding specificity in S100A5 and S100A6.
To determine if altered biological specificity reflects intrinsic specificity changes.

Main Methods:

Quantitative phage display was employed to screen peptide interactions.
30,533 random peptides were tested against human S100A5, S100A6, and their common ancestor (ancA5/A6).
Peptide-binding profiles of modern and ancestral proteins were compared.

Main Results:

Modern S100A5 and S100A6 bound subsets of peptides recognized by ancA5/A6.
Modern proteins also acquired new peptide binding partners not recognized by the ancestor.
ancA5/A6 showed similar specificity to modern proteins when tested against random peptides.

Conclusions:

Altered biological specificity does not necessarily indicate altered intrinsic specificity.
Ancestral reconstruction studies using biological targets should be interpreted cautiously for inferring global evolutionary trends.
The evolution of protein specificity is complex and context-dependent.