# Regulation mechanisms of ABC transporters

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $306,969

## Abstract

PROJECT SUMMARY
This proposal seeks to understand how proteins located in the cell membrane work as gatekeepers to
selectively allow compounds into or out of the cell. Such gatekeepers are known as or ATP-binding
cassette (ABC) transporters, because they use the energy of ATP (adenosine triphosphate) hydrolysis
to transport compounds across the cell membrane. Bacterial ABC importers are essential for
organism survival, controlling the rate of uptake for nutrients scavenged from the bacterium's
environment. Control of the rate of transport precludes over-accumulation of a nutrient that is
beneficial at low concentrations, but is potentially toxic at high concentrations. While a subset of ABC
proteins contain an additional “accessory” domain that can regulate the uptake of compounds by
shutting off the transporter, it is unclear why certain transporters contain these domains while others
do not. However, we do understand that certain transporters are “turned off” when a specific
compound or protein binds to this accessory domain. Other accessory domains regulate by “sensing”
changes in the microenvironment and reacting accordingly. To decipher this mechanism of regulation,
the PI's laboratory combines biochemical and biophysical experiments with structural biology to
understand how these accessory domains play a role in transport regulation, which in restricts or
allows nutrients to enter the cell. This research program will define the molecular mechanism that
controls nutrient uptake and allow researchers to understand how multiple transport systems work in
concert within an organism to maintain cell survival. We will test our hypothesis that regulation of
transporter activation via a sensing accessory protein. The proposed research will decipher the
complex circuitry of regulation in a model system in three Aims to: (1) understand how PepT SBPs
select for different substrates within the microenvironment (i.e., nutrients, cofactors and peptides); (2)
determine how the assembly of the core transporter dictates transport selectivity and efficiency (3)
reveal how PepT transporters regulate the import of substrates into the cell through the activation of a
novel regulatory domain. This research program has set out to close critical gaps in the understanding
of the fundamentals of the transport mechanism present in all bacteria. The results will yield insights
into how regulatory domains modulate transport across all organisms, crucial for cell viability.

## Key facts

- **NIH application ID:** 10143784
- **Project number:** 1R01GM140584-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Heather Wendy Pinkett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,969
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143784

## Citation

> US National Institutes of Health, RePORTER application 10143784, Regulation mechanisms of ABC transporters (1R01GM140584-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10143784. Licensed CC0.

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