Document Type

Dissertation - Open Access

Award Date

2020

Degree Name

Doctor of Philosophy (PhD)

Department / School

Chemistry and Biochemistry

First Advisor

Suvobrata Chakravarty

Keywords

Chromatin signaling, Effects of Mutation in human disorder, PHD finger, Protein folding, Protein-Protein Interaction

Abstract

Plant homeodomain (PHD), a Zinc-finger scaffold, is a conserved protein module in eukaryotes that typically recognizes unstructured histone tails, and thus, PHDs play a crucial role in chromatin signaling. The sequences of Zinc-fingers, in general, diversify during the course of evolution often giving rise to subtypes (e.g., RBR-RING (Dove 2017) or zf-CxxC subtypes (Long 2013) who typically contain specific sequence signatures. We recently discovered that PHD fingers also contain a distinct subtype, namely the xCDxCDx-PHD. xCDxCDx-PHD has a distinct composition of specific amino acids that coevolved (coevolving residues) in the course of evolution, and xCDxCDx-PHD also shows a unique mechanism for interacting with histone H3 (i.e., unique function). It, however, is unclear if the set of coevolving residues were selected by nature exclusively for function alone or the selection was for the maintenance of the structure, stability and/or dynamics in order to perform the specific function. Here, we systematically characterize the contributions of the evolving residues in the PHD scaffold with detailed experimentation (e.g., using NMR, CD, FASTpp and ITC) to discover that the coevolving residues of xCDxCDx-PHD contribute only towards histone recognition (i.e., function). As somatic and germline mutations of xCDxCDx-PHD are often associated with a number of cancers and inherited diseases, this investigation provides a platform to further probe the consequence of disease-causing mutations in xCDxCDx-PHD.

Library of Congress Subject Headings

Zinc-finger proteins.
DNA-protein interactions.
Chromatin.

Format

application/pdf

Number of Pages

122

Publisher

South Dakota State University

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Included in

Biochemistry Commons

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Rights Statement

In Copyright