# Structure and Mechanism of the Human FE-S Cluster Assembly Complex

> **NIH NIH R01** · TEXAS A&M UNIVERSITY · 2020 · $285,099

## Abstract

Metal ions are essential to life as they augment amino acid protein
chemistry and thereby catalyze many difficult biological reactions. As “free” metal
ions are toxic and indiscriminately reactive, critical protein systems have evolved
to sequester, chaperone, and regulate metal ion concentrations. Defects in these
systems lead to metal ion metabolic disease and result in cellular, tissue, and
systemic pathology. The iron-sulfur cluster assembly pathway contains a
conserved set of proteins that synthesizes Fe-S clusters, which are then
distributed by a network of cluster transfer and conversion factors to hundreds of
Fe-S dependent proteins. Here we focus on the structure of the eukaryotic Fe-S
assembly complex and the mechanism of cluster biosynthesis. We show that a
stable low activity Fe-S assembly complex can be activated by binding of the
Friedreich's ataxia protein (frataxin; FXN), and that the mitochondrial acyl carrier
protein (ACP) has a moonlighting function as a component critical for the stability
and function of the assembly complex. Further, our crystal structure of the core
(NFS1-ISD11-ACP; called SDA) of the eukaryotic Fe-S assembly complex
revealed a dramatically different architecture compared to the prokaryotic system
that is stabilized by a novel ACP-lipid interaction with the hydrophobic core of
ISD11. Here, we will build upon these paradigm shifting results to determine
structural and dynamic information for binding accessory proteins to the SDA
core of the Fe-S assembly complex, elucidate how ACP-lipid interactions
modulate functional properties for the assembly complex, and provide
mechanistic insight into FXN based activation and Fe-S cluster formation. This
fundamental research will establish a framework for emerging genetic results and
discoveries and provide a basis for understanding defects in iron-sulfur cluster
metabolism relevant to human health and disease.

## Key facts

- **NIH application ID:** 9853801
- **Project number:** 5R01GM096100-08
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** DAVID P BARONDEAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,099
- **Award type:** 5
- **Project period:** 2011-09-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853801

## Citation

> US National Institutes of Health, RePORTER application 9853801, Structure and Mechanism of the Human FE-S Cluster Assembly Complex (5R01GM096100-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853801. Licensed CC0.

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