# Mechanisms in COPII-Dependent Transport

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $551,111

## Abstract

Project Summary
Accurate protein transport in the secretory pathway is vital for cell function and growth. Our research
program is focused on coat-dependent sorting mechanisms that drive protein trafficking between the
endoplasmic reticulum (ER) and Golgi complex. Nascent secretory proteins are translated at the ER and
then fully folded proteins are selectively packaged into COPII coated vesicles for anterograde transport to
the Golgi complex. This forward pathway is balanced by retrograde transport from the Golgi, which
selectively returns proteins to the ER in COPI coated vesicles. To ensure delivery of only folded secretory
proteins, a process known as ER quality control largely retains nascent proteins in the ER until correctly
folded or targets terminally misfolded proteins for degradation. The coordinated mechanisms that maintain
organelle identity, advance folded biosynthetic cargo and retain misfolded proteins are not well understood.
We identified a set of transmembrane cargo receptors that function in coat-dependent sorting and quality
control in the early secretory pathway. This research plan will address key questions on how cargo receptors
recognize their clients and catalyze net directional traffic of proteins. In the past funding period, we
characterized the Erv41-Erv46 complex as a retrograde receptor that retrieves ER-resident proteins through
the activity of a conserved thioredoxin-like domain in Erv46. Our recent findings indicate the Erv41-Erv46
receptor also retrieves misfolded secretory proteins that have exited the ER. The specific aims of this
proposal will test the molecular model that the Erv46 subunit recognizes hydrophobic features displayed by
escaped cargo in the low pH environment of Golgi compartments. After return to the ER, redox activity on
the Erv46 thioredoxin-like domain releases bound cargo from the receptor at neutral pH. Through these
mechanisms, pH and redox gradients drive efficient protein sorting in the early secretory pathway. This
model will be tested in the following experimental aims. Aim 1: Define the molecular mechanisms of Erv41-
Erv46 cargo binding at reduced pH of the Golgi compartment. Aim 2: Determine the mechanism by which
cargo is efficiently released from Erv41-Erv46 in the ER. Aim 3: Test the model that Erv41-Erv46 recognizes
and binds directly to misfolded cargo for active retrieval to the ER. We will rigorously test our models by
exploiting iterative genetic, cellular and biochemical approaches to monitor protein function in vivo, in cell
free assays and in reconstitution experiments with purified factors. Defining the molecular mechanisms that
underlie conserved protein sorting processes will provide fundamental insights on cellular organization and
contribute to treatments for human diseases connected to secretory pathway function.

## Key facts

- **NIH application ID:** 10210950
- **Project number:** 2R01GM052549-27
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** CHARLES K BARLOWE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,111
- **Award type:** 2
- **Project period:** 1995-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210950

## Citation

> US National Institutes of Health, RePORTER application 10210950, Mechanisms in COPII-Dependent Transport (2R01GM052549-27). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10210950. Licensed CC0.

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