# MECHANISMS OF AP-3 FUNCTION IN VESICLE FORMATION AND GOLGI MATURATION

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $470,017

## Abstract

PROJECT SUMMARY
The secretory pathway folds, assembles, and sorts membrane and secreted proteins and targets them to a
variety of locations inside and outside the cell. The `Grand Central Station' of the cell is the trans Golgi network
(TGN), an incredibly dynamic and complex structure that packages cargo into separate containers and dispatches them to their terminal destinations. The AP-3 trafficking complex sorts cargo from endosomes or the
Golgi into containers bound for endolysosomal compartments, bypassing the endosomal multivesicular body
and ESCRT pathway. AP-3 is needed for productive assembly of HIV and other viral capsids. Genetic lesions
impairing AP-3 function cause multiple diseases, including Hermansky-Pudlak Syndrome type 2 and an epilepsy-like syndrome. Despite its importance, remarkably little is known about the mechanisms of AP-3 function.
In this collaborative Project, we exploit published and unpublished genetic, cell biological, and biochemical advances, and employ state of the art imaging approaches, to dissect the mechanisms of AP-3 budding and the
consequences of AP-3 function for the overall dynamics of the TGN, in the model organism Saccharomyces
cerevisiae. In Aim 1, we build on proteomic surveys, functional genomic surveys, and follow-up analyses, wich
identify new candidate AP-3 cofactors including a ubiquitin ligase. We will use these advances to test hypotheses about the assembly, maturation, and dispatch of AP-3 vesicles from the TGN. In Aim 2, we build on
preliminary findings showing that disruption of AP-3 activity causes striking and unexpected global perturbations of Golgi architecture. We hypothesize, based on published and unpublished data, that distinct carriers
exit the TGN in a programmed, sequential manner, with AP-3 carriers departing early. We will further test this
model and dissect the molecular mechanisms though which the sequence of events is programmed. Together,
these studies should establish new paradigms for AP-3 vesicle formation and for organelle maturation dynamics in the Golgi-endolysosomal system.

## Key facts

- **NIH application ID:** 10017291
- **Project number:** 5R01GM130644-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Alexey Jarrell Merz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,017
- **Award type:** 5
- **Project period:** 2019-09-12 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017291

## Citation

> US National Institutes of Health, RePORTER application 10017291, MECHANISMS OF AP-3 FUNCTION IN VESICLE FORMATION AND GOLGI MATURATION (5R01GM130644-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017291. Licensed CC0.

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