# Mechanisms and Physiology of COPI Transport

> **NIH NIH R37** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $581,750

## Abstract

We have been at the forefront in elucidating the mechanisms and physiology of Coat Protein I (COPI)
transport. We are proposing four lines of future investigation to maintain this track record of achievement.
First, following up on our recent discovery that COPI generates not only vesicles but also tubules, and the
small GTPase Cdc42 promotes COPI tubule formation through an intrinsic ability to bend membrane, we
will elucidate how Cdc42 achieves this remarkable feat. In addition, as Cdc42 belongs to the Rho family of
small GTPases, and we have found that other Rho members also affect COPI transport, we will elucidate
how they could affect COPI vesicle and tubule formation. Second, we will address a current controversy
regarding how COPI bends membrane. Whereas coat proteins are predicted to assemble into protein
lattices with regular geometry in bending membrane, COPI has been found recently to assemble into
lattices with irregular geometry. We will examine whether this apparent exception is due to the
reconstitution of COPI vesicles that has thus far not accounted for all the factors needed for a physiology
reconstitution of COPI vesicles. Third, we will follow up on our recent discovery that has identified a novel
role for a ciliary protein, known as IFT20. We have found that IFT20 exists at the Golgi, where it promotes
COPI tubular transport. Thus, we will elucidate how IFT20 exerts this novel role. Fourth, we will elucidate
how a point mutation in a core component of the COPI complex, known as yl-COP, leads to
immunodeficiency in affected individuals. We have already elucidated one explanation, which involves
defect in COPI binding to the KDEL receptor, leading to stress in the endoplasmic reticulum (ER) to impair
the function of T and B cells. However, because COPI binds to other cargo proteins, including a large
family of proteins that promote exit from the ER, known as ER cargo receptors, we will identify those ER
cargo receptors affected by the yl-COP mutation and then elucidate how their defective binding by COPI
 leads to altered cellular functions. In addition, as we have found that the y l -COP mutation also impairs
COPI tubular transport, we will elucidate a mechanistic explanation for this additional effect of the mutation.
We anticipate that the completion of these four aims will advance a basic understanding of how COPI acts
to generate transport carriers, as well shed physiologic insights into cellular processes that requires this
transport.
RELEVANCE (See instructions):
We study how proteins and membranes are transported in the cell , a process known as intracellular
transport. We have been focusing on the initial step of this process that involves the generation of
transport carriers. As intracellular transport is a fundamental process that is required for proper cellular
function, we anticipate that the results of our proposed studies will contribute to a better understanding of
disease mechanisms.

## Key facts

- **NIH application ID:** 9970634
- **Project number:** 4R37GM058615-19
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** VICTOR W HSU
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $581,750
- **Award type:** 4C
- **Project period:** 2001-02-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970634

## Citation

> US National Institutes of Health, RePORTER application 9970634, Mechanisms and Physiology of COPI Transport (4R37GM058615-19). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970634. Licensed CC0.

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