# Heparan sulfate co-polymerase function and defects in disease

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2024 · $332,957

## Abstract

Proteoglycans harboring heparan sulfate (HS) chains are widely found on cell surfaces and in extracellular
matrices where they interact with growth factors, receptors, morphogens, and extracellular matrix components
and play critical roles in processes such as cell survival, division, migration, differentiation, pathogen binding,
and cancer development. HS biosynthesis is a complex process involving initial formation of a linker glycan on
proteoglycan core proteins, priming and extension of the HS chains’ polymer backbone, and subsequent
modification by epimerization, and N- and O-sulfation. The extension of the polymer backbone is a crucial step
in HS synthesis, facilitated by the EXT1-EXT2 heterodimeric co-polymerase complex. Homozygous defects in
either of these proteins cause embryonic lethality, and heterozygous loss of function results in hereditary multiple
exostoses (HME) characterized by clinical features in bone, cartilage, ligaments, and subepithelial layers,
including the formation of benign cartilage-capped tumors. We recently solved the structure of the human EXT1-
2 heterodimeric co-polymerase in complex with substrate analogs and performed complementary enzymatic
studies on both wild type and mutant enzymes to gain insights into HS chain synthesis. EXT1 and EXT2 form
an obligate heterocomplex of the two homologous proteins. Each protein contains two separate predicted
catalytic domains, yet only one of the two domains are active in each protein suggesting that the monomers
share catalytic functions. We also discovered an interaction between EXT1-2 and the HS priming enzyme
EXTL3. These studies raise important new questions about how HS synthesis is achieved in vivo and the nature
and pathology of HME mutations. The prior accomplishments set the stage for our present aims. Aim 1 will test
hypotheses regarding EXT1-2 active site residues by probing their roles in substrate recognition and catalysis
and the roles of divergent residues in the inactive homologous domains that restrict catalysis. Aim 2 will test
hypotheses on how HME mutations lead to EXT1-2 loss of function and how haploinsufficiency leads to HS loss
and pathology. Aim 3 will test hypotheses that interactions with proteoglycan core proteins and upstream
biosynthetic enzymes contribute to efficient HS synthesis. Thus, this research will advance our understanding of
HS biology and its roles in health and disease. Unraveling the mechanisms governing HS backbone synthesis
will shed light on the molecular basis of HS-mediated cellular processes and pave the way for future development
of targeted interventions.

## Key facts

- **NIH application ID:** 10937607
- **Project number:** 1R01GM154846-01
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** KELLEY W. MOREMEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $332,957
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937607

## Citation

> US National Institutes of Health, RePORTER application 10937607, Heparan sulfate co-polymerase function and defects in disease (1R01GM154846-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10937607. Licensed CC0.

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