# Cellular and molecular mechanisms regulating function of a broadly conserved gamete membrane fusogen

> **NIH NIH F32** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $19,671

## Abstract

Project Summary
Our understanding of the molecular mechanisms of fusion between reproductive cells (gametes)
during sexual reproduction is surprisingly limited. In studies with the unicellular green alga,
Chlamydomonas and the malaria pathogen Plasmodium, the Snell laboratory has shown that the
broadly conserved, gamete-specific membrane protein HAP2 (also called GCS1) is essential for
bilayer merger during gamete fusion. HAP2 acts after tight adhesion of gamete plasma
membranes, and is present on only one of the two gametes (e.g., mating type minus gametes in
Chlamydomonas) and therefore functions unilaterally, as do viral fusion proteins during their entry
into host cells. Remarkably, recent collaborative structure/function studies demonstrated that
Chlamydomonas HAP2 is structurally homologous to the class II fusion proteins of many
enveloped viruses, including dengue and Zika. Though recombinant forms of the ectodomain of
Chlamydomonas HAP2 form trimers in vitro and the hydrophobic fusion loop is essential for
function in vivo, we still know very little about the molecular mechanism of this eukaryotic class
II fusion protein during gamete fusion in any HAP2 organism. Endogenous trimers that
presumably form during gamete fusion have yet to be detected, and the mechanisms are
unknown that restrict triggering of trimer formation until the HAP2-bearing gamete undergoes
specific membrane interaction with the membrane of its partner gamete. In preliminary
experiments, I have discovered a stable oligomer, which appears only after gamete fusion, and is
likely to be the endogenous HAP2 trimer. I have also determined that, unlike with the viral class
II proteins, low pH fails to trigger oligomer formation of HAP2. Rather, the HAP2-containing
minus mating structure must bind to the adhesion protein FUS1 on the plus mating structure,
ensuring that triggering takes place only at the right time and place. This research aims to define
the molecular mechanisms that underlie the function of a broadly conserved eukaryotic
membrane fusogen that is essential for fusion of gametes in organisms across kingdoms. The
insights gained from this study will improve our understanding of fundamental, conserved
mechanisms of gamete fusion, and have the potential to yield improved strategies for interfering
with sexual reproduction and transmission of organism that harm humans, including the
devastating malaria organism Plasmodium. Here, I will test the model that a new HAP2 oligomer
detected in gametes after fusion is a trimer. I will investigate structural features of HAP2 required
for oligomerization. And, I will investigate the mechanisms that underlie FUS1-dependent
triggering of HAP2 structural rearrangements.

## Key facts

- **NIH application ID:** 10228351
- **Project number:** 3F32GM133158-01S1
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Jun Zhang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $19,671
- **Award type:** 3
- **Project period:** 2019-09-09 → 2020-12-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228351

## Citation

> US National Institutes of Health, RePORTER application 10228351, Cellular and molecular mechanisms regulating function of a broadly conserved gamete membrane fusogen (3F32GM133158-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10228351. Licensed CC0.

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