CHARACTERIZATION OF MUSK BINDING TO TYPE 1 BMP RECEPTORS

Gad, Mark

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Year:: 2021
Contributor:: Gad, Mark (creator); Fallon, Justin (Advisor); Jaworski, Alex (Reader); Fawzi, Nicolas (Reader); Brown University. Department of Molecular Pharmacology, Physiology and Biotechnology (sponsor)
Genre:: theses
Subject:: Bone morphogenetic proteins; Muscle cells; MuSK; BMP receptors
Extent:: vii, 47 p.

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Abstract:: Bone Morphogenetic Proteins (BMPs) are present almost everywhere in the body. They have various functions, which makes the question of how the BMP signal is modulated in a tissue-specific manner intriguing. Our lab recently reported that MuSK is a BMP co-receptor and binds BMPs via the Ig3 domain. We also reported that MuSK not only binds BMPs but also binds type 1 BMP receptors (BMPR1A and BMPR1B). Despite the importance of the BMP pathway and its modulators, little is known about the interaction between MuSK and Type 1 BMP receptors. This thesis addresses how BMP receptors interact with Muscle-specific Kinase (MuSK), a receptor tyrosine kinase that is highly enriched in muscle tissue. My project aimed to map the domain(s) of MuSK that is/are necessary to bind to BMPR1. We hypothesized that MuSK-BMPR1 binding is a potential regulatory mechanism of BMP signaling. To achieve my goal of characterizing the MuSK-BMPR1 interaction, I, alongside a Ph.D. student in the lab, designed and generated different His-tagged deletion constructs of the MuSK ectodomain as well as isolated domains. I used a solid-phase binding assay to measure the binding of BMPR1A and BMPR1b to different MuSK constructs and generate binding curves for each construct. After testing more than ten different deletion constructs and isolated domains, I successfully identified a single domain (Ig2) required for MuSK-BMPR1 binding. I was able to show that this particular domain is sufficient and necessary for binding BMPR1. I made two other findings alongside this critical finding: (1) I tested the binding of MuSK to BMP receptors under different pH conditions and showed the MuSK binding to BMPR1 is pH-dependent. (2) I showed that the Ig1 domain is not necessary for MuSK binding to Type 1 BMP receptor. Characterization of the MuSK-BMPR1 interaction is significant because it can potentially be used to support a therapeutic development program targeting the MuSK-BMP pathway for AD. To develop a drug that targets this pathway, a complete understanding of all the interactions and binding partners of MuSK is necessary.
Notes:: Thesis (Sc. M.)--Brown University, 2021

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Citation

Gad, Mark, "CHARACTERIZATION OF MUSK BINDING TO TYPE 1 BMP RECEPTORS" (2021). Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:t6becdrw/

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Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations

Theses and Dissertations for the Molecular Pharmacology, Physiology, and Biotechnology department.
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