# Mechanisms regulating proteasomal substrate degradation

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2021 · $304,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The Ubiquitin Proteasome System (UPS) regulates the degradation of the majority of proteins in the cell and, as such, it is
involved in essentially every cellular process. Because of its central role, misregulation within the UPS can potentiate or
cause diseases, such as neurodegeneration and cancer. It is now well understood that protein misfolding and
accumulation, which are intimately associated with neurodegenerative disease, can impair the UPS, exacerbating the
disease. In fact, there is great interest to find ways of activating proteasome function as possible treatments for
neurodegenerative disorders. To the contrary, in neoplastic disease the UPS is often exploited and even upregulated; due
to this, a first line treatment for multiple myeloma is proteasome inhibition. The UPS thus sits at a shared and critical
position in these two major human diseases. The proteasome—the central degradative machinery of the UPS—is
regulated by very different regulatory complexes (e.g. 19S, PA28, PA28, PA200, and putatively P97). The job of these
complexes is to regulate the function of the core particle of the proteasome, the 20S, which isolates its protein degradation
chamber from the cellular milieu. A commonality shared by these regulators is that they all function to induce opening of
the 20S proteasome substrate gate, which exposes substrates to the interior degradation chamber. The proteasome, and
its regulators, provide a rich regulatory landscape to develop therapies that could profoundly impact these two large fields
of study. This will require a deep biochemical understanding of the involved molecular mechanisms. The recent barrage
of proteasomal structures facilitate this effort, but structures without an understanding of the dynamic mechanisms that
underlie their functions are limited. Therefore, this proposal is primarily focused on understanding the biochemical
function of three of these diverse proteasomal complexes and defining how they regulate protein degradation. We will
focus on three specific questions: 1) How do the N-terminal domains of the proteasomal ATPases affect proteasome
function?, 2) How does the mammalian P97 function to stimulate protein degradation by the 20S proteasome?, and 3)
How does PA28 regulate 20S function to catalyze nuclear protein degradation? We have chosen to focus on these three
regulators because they each play unique roles in the types of substrates that they degrade, and they each play key roles
in specific human diseases. We implement a variety of approaches and systems to address these questions including
studying function of proteasomal regulators from archaea, yeast, nematodes, mammals, and humans. Furthermore, we
are using C. elegans as an animal model system to test our biochemically derived models and genetically test therapeutic
concepts. The successful completion of this study will produce a sustained impact in the field by defining the central
mechanisms of these th...

## Key facts

- **NIH application ID:** 10247747
- **Project number:** 5R01GM107129-08
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** David Matthew Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $304,000
- **Award type:** 5
- **Project period:** 2014-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247747

## Citation

> US National Institutes of Health, RePORTER application 10247747, Mechanisms regulating proteasomal substrate degradation (5R01GM107129-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247747. Licensed CC0.

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