Date of Graduation

12-2016

Document Type

Thesis (MS)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Zheng Chen, PhD

Committee Member

Andrew Bean, PhD

Committee Member

Carmen Dessauer, PhD

Committee Member

Darren Boehning, PhD

Committee Member

Seung-hee Yoo, PhD

Abstract

Ubiquitin-mediated proteasomal degradation is an essential cellular function that is coordinated by three key components: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligases. There are an estimated 600 E3 ligases, some of which share high sequence homology; however, the functional significance often remains unknown. FBXL3 and FBXL21 are two homologous E3 ligases that have previously been reported to dictate circadian periodicity, with FBXL3 being the dominant E3 ligase and FBXL21 playing a regulatory role. A recent Yeast Two-Hybrid screen revealed a new shared target of FBXL3 and FBXL21: Telethonin (also known as TCAP). TCAP is a sarcomeric z-disc protein expressed in cardiac and skeletal muscle that is critical to proper structure and function of muscles. Through preliminary experiments, we identified TCAP as a novel shared target substrate of FBXL3 and FBXL21. Here we report that FBXL3 and FBXL21 both accelerate TCAP degradation; however, FBXL21 is the more potent E3 ligase. This novel finding underlines the importance of substrate specificity and serves as a paradigm for future mechanistic studies of E3 ligase homologous pairs. Additionally, the findings reported here will facilitate further studies investigating the role of FBXL3/21 in muscle physiology.

Keywords

FBXL3, FBXL21, E3 ligases, circadian, muscle, protein degradation

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