Open AccessNanobodies as allosteric modulators of Parkinson’s disease–associated LRRK2
Author(s) -
Ranjan K. Singh,
Ahmed Soliman,
Giambattista Guaitoli,
Eliza Störmer,
Felix von Zweydorf,
Thomas Dal Maso,
Asmaa Oun,
Laura Van Rillaer,
Sibylle Schmidt,
Deep Chatterjee,
Joshua A. David,
Els Pardon,
Thomas Schwartz,
Stefan Knapp,
Eileen J. Kennedy,
Jan Steyaert,
Friedrich W. Herberg,
Arjan Kortholt,
Christian Johannes Gloeckner,
Wim Versées
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2112712119
Subject(s) - lrrk2 , protein kinase domain , allosteric regulation , kinase , biology , microbiology and biotechnology , rab , phosphorylation , leucine rich repeat , biochemistry , chemistry , gtpase , mutation , gene , enzyme , mutant
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.