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The Evolution of Metal and Peptide Binding in the S100 Protein Family

Proteins perform an incredible array of functions facilitated by a diverse

set of biochemical properties. Changing these properties is an essential molecular

mechanism of evolutionary change, with major questions in protein evolution

surrounding this topic. How do new functional biochemical features evolve? How

do proteins change following gene duplication events? I used the S100 protein

family as a model to probe these aspects of protein evolution. The S100s are

signaling proteins that play a diverse range of biological roles binding Calcium

ions, transition metal ions, and other proteins. Calcium drives a conformational

change allowing S100s to bind to diverse peptide regions of target proteins. I used

a phylogenetic approach to understand the evolution of these diverse biochemical

features. Chapter I comprises an introduction to the disseration. Chapter II is

a co-authored literature review assessing available evidence for global trends in

protein evolution. Chapter III describes mapping of transition metal binding

onto a maximum likelihood S100 phylogeny. Transition metal binding sites and

metal-driven structural changes are a conserved, ancestral features of the S100s.

However, they are highly labile at the amino acid level. Chapter IV further characterizes the biophysics of metal binding in the S100A5 lineage, revealing

that the oft–cited Ca2+/Cu2+ antagonism of S100A5 is likely due to an experimental

artifact of previous studies. Chapter V uses the S100 family to investigate the

evolution of binding specificity. Binding specificity for a small set of peptides

in the duplicate S100A5 and S100A6 clades. Ancestral sequence reconstruction

reveals a pattern of clade-level conservation and apparent subfunctionalization

along both lineages. In chapter VI, peptide phage display, deep-sequencing, and

machine-learning are combined to quantitatively reconstruct the evolution of

specificity in S100A5 and S100A6. S100A5 has subfunctionalized from the ancestor,

while S100A6 specificity has shifted. The importance of unbiased approaches to

measure specificity are discussed. This work highlights the lability of conserved

functions at the biochemical level, and measures changes in specificity following

gene duplication. Chapter VII summarizes the results of the dissertation, considers

the implications of these results, and discusses limitations and future directions.

This dissertation includes both previously published/unpublished and co-

authored material.

Identiferoai:union.ndltd.org:uoregon.edu/oai:scholarsbank.uoregon.edu:1794/23178
Date10 April 2018
CreatorsWheeler, Lucas
ContributorsHarms, Michael
PublisherUniversity of Oregon
Source SetsUniversity of Oregon
Languageen_US
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation
RightsAll Rights Reserved.

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