# Molecular Mechanisms of the Type I Secretion System from Bacterial Pathogens

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $351,750

## Abstract

ABSTRACT
Protein secretion is an essential component of the arsenal used by many bacterial pathogens to
invade hosts, damage tissues, and suppress immune responses. Gram-negative bacteria have
evolved sophisticated machines to secrete proteins across two membranes: the inner
membrane and outer membrane. Since discovered in 1979, the type I secretion system (T1SS)
has been identified in more than 800 bacterial genomes, and many of its substrates contribute
to the virulence of pathogens, examples being hemolysin HlyA in uropathogenic Escherichia coli,
adhesin SiiE in Salmonella enterica, and adenylate cyclase CyaA in Bordetella pertussis. The
T1SS secretes unfolded substrates from the cytoplasm to the extracellular milieu. It includes
three components: an ATP-binding cassette transporter (ABC transporter), associated
periplasmic adapter proteins located in the inner membrane, and a porin in the outer membrane.
The canonical “alternating access” model cannot explain how the large protein substrates are
transported by the T1SS ABC transporter across the inner membrane. Therefore, the
mechanisms of substrate secretion at the molecular level is still obscure. The proposed
research leverages single particle cryo-electron microscopy (cryoEM), bioinformatics, in vivo
and in vitro assays to answer key questions in the field, including the structural basis of
substrate recognition, the nature of the translocation pathway, the energetics for substrate
translocation, and the regulation of the T1SS ABC transporter's activity. The studies will
substantially increase the fundamental scientific knowledge about the mechanisms of the T1SS
and provide a new basis for developing future therapeutic interventions against a broad range of
bacterial infections.

## Key facts

- **NIH application ID:** 10455607
- **Project number:** 5R01GM137068-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Wei Mi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,750
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455607

## Citation

> US National Institutes of Health, RePORTER application 10455607, Molecular Mechanisms of the Type I Secretion System from Bacterial Pathogens (5R01GM137068-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455607. Licensed CC0.

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