# The GID Ubiquitin Ligase and the Pro/N-End Rule Pathway in Yeast and Mammals

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $604,650

## 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 the ubiquitin-dependent N-end rule pathway
over the last three decades were made possible, to a large extent, by the present grant (DK039520-30),
currently in its 31st year of support. The N-end rule pathway recognizes proteins containing N-terminal
degradation signals called N-degrons, polyubiquitylates these proteins and thereby causes their
degradation by the proteasome. Recognition components of the N-end rule pathway are called N-recognins.
In eukaryotes, N-recognins are E3 ubiquitin ligases that can target N-degrons. The eukaryotic N-end rule
pathway consists of three branches. The first branch, called the Arg/N-end rule pathway, targets specific
unacetylated N-terminal residues of protein substrates. This branch, discovered by our laboratory in 1986,
continues to be a fount of biological insights. The second branch, called the Ac/N-end rule pathway, was
discovered by our laboratory in 2010. This pathway recognizes proteins that bear N-terminally acetylated
residues. The third branch of the N-end rule pathway, termed the Pro/N-end rule pathway, has emerged
through unpublished studies, over the last two years, by our laboratory. This proteolytic pathway is
mediated by the previously known ubiquitin ligase called GID and recognizes the N-terminal proline (Pro)
residue of a protein and an adjoining sequence motif.
 The present (DK039520) renewal application focuses on these (latest) advances and the largely
unexplored Pro/N-end rule pathway, in both yeast and mammals. Its biological functions include the
regulation of physiologically important transitions between cellular states that require de novo synthesis of
glucose (for example, starvation or semi-starvation states) and conditions of ample glucose availability. The
Pro/N-end rule pathway has other functions as well, which are beginning to emerge, in part through our
recent identification of non-gluconeogenic proteins that are either targeted by or interact with the Pro/N-end
rule pathway, in both yeast and mammals. These and related yeast and mammalian studies, described in
Specific Aims of the present renewal application, will advance the understanding of protein degradation and
the universally present N-end rule pathway.

## Key facts

- **NIH application ID:** 9963196
- **Project number:** 5R01DK039520-33
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ALEXANDER J VARSHAVSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $604,650
- **Award type:** 5
- **Project period:** 1995-02-11 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963196

## Citation

> US National Institutes of Health, RePORTER application 9963196, The GID Ubiquitin Ligase and the Pro/N-End Rule Pathway in Yeast and Mammals (5R01DK039520-33). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963196. Licensed CC0.

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