# Protein quality control at eukaryotic membranes

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $402,428

## Abstract

Project Summary/Abstract
Integral membrane protein quality control systems are present within every major eukaryotic organelle. The
archetypal integral membrane protein quality control system is called Endoplasmic reticulum-associated
degradation (ERAD). For ERAD, ER proteins are degraded, either because they are misfolded or because their
degradation is physiologically regulated. While its primary function is to target misfolded or regulated proteins,
ERAD also functions to alleviate ER stress and is exploited by bacterial and viral pathogens to gain access to
the cytosol and degrade host cell immune complexes. During normal ERAD, protein targets are selected within
the ER lumen and transported across the membrane to the cytosol (retrotranslocation). Once in the cytosol, the
targets are polyubiquitinated, extracted/dislocated from the membrane, and degraded by the proteasome. Even
with decades of genetic, biochemical, and structural data, many aspects of ERAD remain ambiguous. Currently,
basic information like the degrons that target substrates to the ERAD system, the mechanics for how ERAD
interacts with target proteins, and even the range of cellular pathways under the control of ERAD are mysterious.
The goals of this proposal are to: 1) define the features of targets directing them to ERAD (the degrons), 2)
determine how the ERAD system recognizes, and retrotranslocates, target proteins across the ER membrane,
3) understand how the membrane composition controls ERAD function, 4) dissect the mechanics of other (non-
ERAD) integral membrane protein quality control systems. We will use a multifaceted approach with
biochemistry, cell biology, and genetics to address these central questions in membrane-associated protein
quality control. We will leverage our unique in vivo and in vitro assays (and continue to design innovative assays)
to dissect the mechanisms of target degradation by eukaryotic systems. A mechanistic understanding of how
these systems function (including ERAD) and the processes they regulate will establish these systems as viable
therapeutic targets in medically relevant pathways of protein misfolding, protein misregulation, and pathogen
hijacking.

## Key facts

- **NIH application ID:** 10764491
- **Project number:** 2R35GM128592-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ryan Douglas Baldridge
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,428
- **Award type:** 2
- **Project period:** 2018-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764491

## Citation

> US National Institutes of Health, RePORTER application 10764491, Protein quality control at eukaryotic membranes (2R35GM128592-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10764491. Licensed CC0.

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