# Structure and function of polyamine transporters

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2024 · $442,982

## Abstract

PROJECT SUMMARY
Polyamines are a class of small organic polycations indispensable for many basic molecular and cellular
processes including translation, electrical signaling, cell proliferation, and autophagy. Infectious and
hyperproliferative diseases as well as many autoimmune, cardiovascular and neurodegenerative disorders are
deeply connected to perturbations in polyamine abundance. Polyamine transport plays a major role in cellular
polyamine homeostasis in both healthy and abnormal cells. Understanding the molecular basis of polyamine
uptake and secretion has enormous potential to improve human health. However, despite decades of work, this
subject continues to mystify. A critical barrier to deeper knowledge in polyamine transport is the complete
absence of atomic structures of any polyamine transporter. The goal of this project is to elucidate the fundamental
principles underlying polyamine transport and its regulation using a combination of structural and functional
approaches. ATP13A2 is a lysosomal P-type ATP-driven pump tasked with the import of spermine and
spermidine from the lysosome lumen to the cytosol. Mutations that cripple ATP13A2 function causes a spectrum
of neurodegenerative diseases including Kufor-Rakeb syndrome, early-onset Parkinson’s disease, hereditary
spastic paraplegia, neuronal ceroid lipofuscinosis and amyotrophic lateral sclerosis. ATP13A2 is, thus, a
potential drug target. We have made significant inroads in our preliminary studies to determine high-resolution
three-dimensional structures of human ATP13A2. In combination with functional analysis, these structures
revealed ATP13A2’s luminal gating and polyamine selectivity mechanisms. Building on these preliminary results,
we will leverage complementary electron cryo-microscopy, biophysical, biochemical, analytical chemical and
mutagenesis strategies to further subject ATP13A2 to detailed mechanistic scrutiny. Specifically, we aim to
investigate: 1) how lipids regulate ATP13A2 activity; 2) whether and how ATP13A2 pumps other cations into the
lysosome; and 3) how ATP13A2 shuttles polyamines through the lipid bilayer. By addressing these questions,
this research project will provide new insights into the basic operating and regulatory mechanisms of ATP13A2,
which will broadly advance our understanding of polyamine transport and lysosome physiology. Structural and
mechanistic discoveries from the proposed work may inform future rational design of therapeutics targeting
ATP13A2.

## Key facts

- **NIH application ID:** 10844609
- **Project number:** 5R01GM145623-03
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Kenneth PK Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,982
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844609

## Citation

> US National Institutes of Health, RePORTER application 10844609, Structure and function of polyamine transporters (5R01GM145623-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10844609. Licensed CC0.

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