# New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2023 · $598,988

## Abstract

Project Summary/Abstract
 Regulated proteolysis by the ubiquitin-proteasome system (ubiquitin system) plays essential roles in
a multitude of biological processes and has major ramifications for human health and disease, including
illnesses that range from cancer and neurodegeneration to cardiovascular syndromes and defects of
immunity. Our studies of the ubiquitin-proteasome system and ubiquitin-dependent N-degron pathways
(previously called “N-end rule pathways”) over more than three decades were made possible, to a large
extent, by the present grant (DK039520), currently in its 34th year of support. N-degron pathways
recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, polyubiquitylate these
proteins and thereby cause their degradation by the proteasome or autophagy. Recognition components of
N-degron pathways, called N-recognins, are E3 ubiquitin ligases that can target N-degrons. One eukaryotic
N-degron pathway, called the Arg/N-degron pathway, targets, in particular, specific unmodified Nt-residues
of protein substrates. Another Nt-proteolytic system, called the Pro/N-degron pathway, recognizes, in
particular, the Nt-proline (Pro) residue of protein substrates.
 This DK039520 renewal application stems from our unpublished studies over the last ~2 years, and
focuses on the yeast (S. cerevisiae) Pro/N-degron and Arg/N-degron pathways, including the functions of
specific aminopeptidases and the recently discovered ability of Ubr1, the E3 of the Arg/N-degron pathway,
to target not only N-degrons but also C-degrons. These and related studies, described in Specific Aims of
the DK039520 renewal application, will advance the understanding of protein degradation and the
universally present (as well as medically significant) N-degron pathways.

## Key facts

- **NIH application ID:** 10596188
- **Project number:** 5R01DK039520-36
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ALEXANDER J VARSHAVSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $598,988
- **Award type:** 5
- **Project period:** 1995-02-11 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596188

## Citation

> US National Institutes of Health, RePORTER application 10596188, New Mechanisms and Functions of the Pro/N Degron and Arg/N-Degron Pathways (5R01DK039520-36). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10596188. Licensed CC0.

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