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Access Type

WSU Access

Date of Award

January 2022

Degree Type


Degree Name



Biochemistry and Molecular Biology

First Advisor

Zhe Yang


SET and MYND domain-containing proteins (SMYD) are a special family of histone lysine methyltransferases with an MYND domain inserted into the catalytic SET domain. Through methylating histone and non-histone targets, SMYD proteins are involved in a variety of physiological and pathological processes, such as chromatin remodeling, gene expression regulation, inflammatory responses, and tumorigenesis. However, it is still unclear how SMYD proteins specifically and selectively methylate substrates and what the behind structural basis is.In this dissertation, I identified a novel allosteric site of SMYD2, paving the way for further understanding of SMYD protein substrate selectivity and methylation networks. When bound to proteins, peptides, and small molecules, this allosteric site might elicit different effects responding to distinct cellular environments. A similar structurally equivalent site also exists in SMYD1 and SMYD3, suggesting the allosteric control may present in SMYD proteins and even the protein lysine methyltransferase superfamily. On the other hand, the inserted MYND domain-mediated interaction with proteins involved in calcium-dependent signaling indicates the potential role of SMYD3 in the calcium-dependent pathways. It further expands the non-catalytic functions of SMYD proteins. However, although SMYD5 structure is still unknown, the N-terminal sequence and the C-terminal tail enriched with glutamic acids absent in other SMYD proteins imply the functional uniqueness of SMYD5. I demonstrated that SMYD5 is a nuclear protein with nuclear localization signal in the N-terminus, and the C-terminal tail is flexible and may affect the thermal stability. The interaction between SMYD5 and protamine, an arginine-rich protein that replaces histones in chromatin condensation in sperm, significantly enhances the thermal stability of SMYD5, indicating a potential role of SMYD5 in spermatogenesis. These findings contribute to understanding the structural and functional relationship of SMYD proteins. Our goal in the future is to promote new paradigms in SMYD protein research while further broadening our understanding of their functional diversity.

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