Nanobodies as allosteric modulators of Parkinson’s disease–associated LRRK2
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pnas.2112712119.pdf
Description
Published version
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2.38 MB
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Checksum (MD5)
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Author(s)
Singh, Ranjan K
Soliman, Ahmed
Guaitoli, Giambattista
Störmer, Eliza
von Zweydorf, Felix
Dal Maso, Thomas
Oun, Asmaa
Van Rillaer, Laura
Schmidt, Sven H
Chatterjee, Deep
Date Issued
2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Citation
Singh, Ranjan K, Soliman, Ahmed, Guaitoli, Giambattista, Störmer, Eliza, von Zweydorf, Felix et al. 2022. "Nanobodies as allosteric modulators of Parkinson’s disease–associated LRRK2." Proceedings of the National Academy of Sciences of the United States of America, 119 (9).
Version
Final published version
Abstract
Significance
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder. Mutations leading to overactivation of LRRK2 are a leading cause of familial PD, and this protein is therefore considered as an appealing target for drug design. Here, we describe the discovery and characterization of a diverse set of LRRK2-targeting nanobodies. A subset of these nanobodies inhibit LRRK2 via a mechanism that differs from the commonly used LRRK2 kinase inhibitors. Importantly, some of these nanobodies selectively inhibit certain LRRK2 activities (Rab phosphorylation) while leaving other activities (autophosphorylation) unaffected. We anticipate that these nanobodies will find multiple applications as research tools and will open up opportunities for the development of new PD diagnostics and therapeutics in parallel to other currently pursued strategies.
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder. Mutations leading to overactivation of LRRK2 are a leading cause of familial PD, and this protein is therefore considered as an appealing target for drug design. Here, we describe the discovery and characterization of a diverse set of LRRK2-targeting nanobodies. A subset of these nanobodies inhibit LRRK2 via a mechanism that differs from the commonly used LRRK2 kinase inhibitors. Importantly, some of these nanobodies selectively inhibit certain LRRK2 activities (Rab phosphorylation) while leaving other activities (autophosphorylation) unaffected. We anticipate that these nanobodies will find multiple applications as research tools and will open up opportunities for the development of new PD diagnostics and therapeutics in parallel to other currently pursued strategies.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1073/PNAS.2112712119
