# Investigating the regulation and substrate processing of ADAMTS13 and ADAMTS7 metalloproteases.

> **NIH NIH R35** · OSU CENTER FOR HEALTH SCIENCES · 2021 · $333,500

## Abstract

Project Summary
This MIRA proposal aims to uncover the regulatory mechanisms and substrates for metalloproteases in the
ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin motifs) family. These proteases are thought
to be involved in many biological processes and some members are known to contribute to important human
diseases. The current study focuses mainly on two members of the ADAMTS family, ADAMTS13 and ADAMTS7.
Project 1 will investigate the allosteric regulation of ADAMTS13, an important regulator of blood clotting. I
recently discovered that ADAMTS13 adopts a quiescent closed conformation and becomes allosterically
activated by its substrate, Von Willebrand Factor (VWF). This proposal outlines a mechanistic approach to study
how allosteric regulation is maintained within ADAMTS13 and disrupted by its interaction with VWF. Leveraging
functional, kinetic, structural and bioinformatic analyses, this project sets to identify the key structural elements
of allosteric regulation in ADAMTS13. The outcomes from this work will improve our understanding of inherited
and acquired blood clotting disorders caused by defects in ADAMTS13. I also anticipate that our investigation of
ADAMTS13 will serve as a model to study the regulation of other ADAMTS proteases. Project 2 focuses on
ADAMTS7, which is known to contribute to coronary artery disease by promoting atherosclerosis and
inflammation. However, the substrate targets of ADAMTS7 and its biochemical properties remain poorly
understood. Previous attempts to address these research questions led to conflicting reports in the literature,
likely due to the poor quality of reagents and tools available to study this novel protease. To circumvent these
challenges, we will utilize novel methods in proteomics, enzymology, and protein-protein interactions to delineate
biochemical properties and ideal substrates for ADAMTS7. Newly identified substrates will form the basis of
novel biochemical tools to investigate ADAMTS7 activity and are necessary for future research goals to screen
for small molecule inhibitors of ADAMTS7 that may have translational applications. Summarily, the study of
ADAMTS13 and ADAMTS7 enzyme catalysis and regulation lay a foundation for our understanding of thrombotic
and bleeding disorders and cardiovascular and inflammatory diseases, and these outcomes can be applied to
study other ADAMTS proteases. More importantly, the MIRA offers the principal investigator an incredible
opportunity to recruit and mentor students and other trainees from diverse backgrounds.

## Key facts

- **NIH application ID:** 10276118
- **Project number:** 1R35GM142926-01
- **Recipient organization:** OSU CENTER FOR HEALTH SCIENCES
- **Principal Investigator:** Joshua Mutambuki Muia
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276118

## Citation

> US National Institutes of Health, RePORTER application 10276118, Investigating the regulation and substrate processing of ADAMTS13 and ADAMTS7 metalloproteases. (1R35GM142926-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10276118. Licensed CC0.

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