Semester

Spring

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Visvanathan Ramamurthy

Committee Member

Andrew Dacks

Committee Member

Elena Pugacheva

Committee Member

Michael Robichaux

Committee Member

Michael Schaller

Committee Member

Saravanan Kolandaivelu

Abstract

Posttranslational glutamylation of protein has emerged as a novel candidate for cellular integrity. In a dynamic process, Tubulin Tyrosine Ligase Like proteins (TTLLs) introduce glutamate groups to their substrates, while Cytosolic Carboxypeptidases members (CCP1-CCP6) remove these glutamate groups. The outcome of this interplay is a wide range of substrates; each is glutamylated to a level crucial for its function.

Protein glutamylation is particularly abundant in neurons and in the axoneme of cilia and flagella. This distribution, along with the correlation between imbalanced glutamylation levels and compromised cellular functions, underscores the significance of protein glutamylation in maintaining cellular viability. However, the precise molecular function of protein glutamylation is not fully understood.

In vision, mutations in both TTLL5 (the enzyme responsible for the addition of a glutamate group) and CCP5 (an enzyme that removes glutamates) are linked to blindness in humans, indicating the vital role of protein glutamylation-deglutamylation in photoreceptor health.

Our study reveals tubulin as a retinal substrate of CCP5. We demonstrate the necessity of tubulin glutamylation in maintaining the integrity of the photoreceptor outer segment, and we establish a link between the structural defect in the outer segment and shortening the photoreceptor axoneme.

Understanding the molecular mechanisms that underlie the role of protein glutamylation in preserving outer segment integrity and axoneme length, as well as its potential impact on photoreceptor protein trafficking, mitochondrial dynamics, and light response pathways, presents challenging questions for future investigation. Answering these questions is essential to comprehend the function of protein glutamylation in visual health and diseases and to explore the potential utilization of the glutamylation code in treating related disease.

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