# Analysis of SULT4A1 in protein interactions

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $408,375

## Abstract

SULT4A1 is an enigma within the cytosolic sulfotransferase (SULT) gene family. Unlike other SULTs, SULT4A1
is selectively expressed in neurons in vertebrate brain and is highly conserved from mammals to fish suggesting
an important conserved function. The human SULT4A1 gene (chr. 22q13.3), has been identified as a
susceptibility gene for schizophrenia and is deleted in select cases of Phelan-McDermid (PMS) syndrome, an
autism spectrum disorder. No drug/xenobiotic sulfating activity with SULT4A1 has been reported. All SULT4A1
isoforms lack 15 aa in loop3 that forms the top of the substrate binding pocket in other SULT isoforms. The
missing 15aa help create a putative interaction site for protein substrates. Mouse SULT4A1-knockout (KO)
models generated in our laboratory revealed SULT4A1's role in several vital neuronal functions. Homozygous
SULT4A1-KO mice lack detectable SULT4A1 in brain and develop severe movement tremor and gait problems
with absence seizures starting post-natal day 7-8. Pups show decreased weight gain, increasing immobility with
tremor and spasticity, and usually die within 4-8 weeks. Heterozygous littermates have decreased SULT4A1
CNS expression and appear normal. This is the first mammalian model demonstrating severe neurological
problems associated with loss of SULT4A1. SULT4A1 protein is expressed in CNS neurons with a unique
subcellular distribution in mitochondrial, microsomal and cytosolic fractions but not nuclei. Our data supports the
hypothesis that SULT4A1 is acting as a chaperone/regulatory protein in neurons via SULT4A1-protein
interactions with a potential unique protein sulfation activity. SULT4A1 expression increases mitochondrial
respiration and protects mouse neurons from H2O2 toxicity. In neurons, SULT4A1 interacts with proteins involved
in mitochondria respiration, and other cellular pathways. The neuronal and stress protective functions of
SULT4A1, and its unique subcellular localization provide the backdrop to investigate the biochemical, structural
and functional properties of SULT4A1 in the genetically tractable yeast model, S. cerevisiae. SULT4A1
expressed in yeast displays a similar subcellular protein distribution as observed in neurons. Also, SULT4A1
expression stimulates yeast colony formation and displays the protective function to oxidative stress induced by
H2O2. Therefore, two specific aims are proposed: Aim 1. To investigate SULT4A1 cellular function and determine
SULT4A1 activity as a protein SULT in yeast. Preliminary data in yeast shows that the protective function and
distribution of SULT4A1 is conserved. We propose that the highly conserved residues around the open catalytic
pocket are responsible for protein interactions and potentially protein sulfation activity. Aim 2. To investigate the
role of the SULT4A1 phosphorylation in protein-protein interactions. Co-immunoprecipitation studies will identify
SULT4A1 protein interactors in yeast. Select SULT4A1 mutants of the conserved Thr phosph...

## Key facts

- **NIH application ID:** 10127737
- **Project number:** 1R21NS116312-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Robert C.A.M. van Waardenburg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,375
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127737

## Citation

> US National Institutes of Health, RePORTER application 10127737, Analysis of SULT4A1 in protein interactions (1R21NS116312-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10127737. Licensed CC0.

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