# Mechanisms of Membrane Fusion

> **NIH NIH R35** · DARTMOUTH COLLEGE · 2024 · $778,879

## Abstract

Project Summary/Abstract
Membrane fusion is essential for cell growth, hormone secretion, neurotransmission,
and cell invasion by pathogens. Membrane fusion mechanisms are conserved from
yeast to humans. We have developed yeast vacuole fusion as a model system,
identifying genes for membrane fusion, establishing an in vitro fusion assay with purified
vacuoles, and purifying each relevant protein and lipid for reconstitution into
proteoliposomes which faithfully reconstitute each aspect of fusion. These studies have
revealed novel elements, most recently: 1. A dazzling array of proteins and lipids which
cooperate for orderly lipid bilayer strain and rearrangement, giving fusion without lysis.
2. The assembly of complexes among membrane-bound proteins termed "SNAREs"
isn't spontaneous, as heretofore believed. Their assembly is actually catalyzed by a
large hexameric complex termed HOPS, which recognizes each of the individual
SNAREs and assembles them in active intermediates, poised for rapid fusion. 3.
Chaperones to the SNAREs, termed NSF/Sec18 and aSNAP/Sec17, which had been
believed to only function to disassemble SNARE complexes after fusion, also promote
fusion. 4. Lipids have a vital and active role in fusion. Each of these mechanistic
insights will be pursued; our goals for the next 5 years are to understand the
intermediates of HOPS-catalyzed SNARE assembly, their structures, the roles of
chaperones Sec17/Sec18, and how these proteins trigger the lipid rearrangements of
fusion. The importance of understanding this pathway is underscored by the central role
of HOPS in the invasion of human cells by pathogenic viruses and bacteria.

## Key facts

- **NIH application ID:** 10861767
- **Project number:** 5R35GM118037-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** WILLIAM Tobey WICKNER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $778,879
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861767

## Citation

> US National Institutes of Health, RePORTER application 10861767, Mechanisms of Membrane Fusion (5R35GM118037-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861767. Licensed CC0.

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