Evaluation of the Role of Tanshinone I in an In Vitro System of Charcot-Marie-Tooth Disease Type 2N.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Abietanes*/pharmacology ; Charcot-Marie-Tooth Disease*/metabolism ; Charcot-Marie-Tooth Disease*/genetics ; Charcot-Marie-Tooth Disease*/drug therapy ; Molecular Docking Simulation*; Humans ; Mutation ; Neuropilin-1/metabolism ; Neuropilin-1/genetics ; Neuropilin-1/chemistry ; Protein Binding ; Molecular Dynamics Simulation

Charcot-Marie-Tooth disease type 2N (CMT2N) is an inherited nerve disorder caused by mutations in the alanyl-tRNA synthetase (AlaRS) gene, resulting in muscle weakness and sensory issues. Currently, there is no cure for CMT2N. Here, we found that all five AlaRS mutations in the aminoacylation domain can interact with neuropilin-1 (Nrp1), which is consistent with our previous findings. Interestingly, three of these mutations did not affect alanine activation activity. We then performed a high-throughput screen of 2000 small molecules targeting the prevalent R329H mutant. Using thermal stability assays (TSA), biolayer interferometry (BLI), ATP consumption, and proteolysis assays, we identified Tanshinone I as a compound that binds to and modifies the conformation of the R329H mutant and other CMT-related AlaRS mutants interacting with Nrp1. Molecular docking and dynamic simulation studies further clarified Tanshinone I's binding mode, indicating its potential against various AlaRS mutants. Furthermore, co-immunoprecipitation (Co-IP) and pull-down assays showed that Tanshinone I significantly reduces the binding of AlaRS mutants to Nrp1. Collectively, these findings suggest that Tanshinone I, by altering the conformation of mutant proteins, disrupts the pathological interaction between AlaRS CMT mutants and Nrp1, potentially restoring normal Nrp1 function. This makes Tanshinone I a promising therapeutic candidate for CMT2N.

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2021B1515020047 Guangdong Natural Science Foundation; 32271314 National Natural Science Foundation of China; ZDSYS20230626091203007 Shenzhen Science and Technology Innovation Commission

Keywords: Charcot Marie Tooth disease; Tanshinone I; alanyl-tRNA synthetase

0 (Abietanes)
03UUH3J385 (tanshinone)
144713-63-3 (Neuropilin-1)

Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241028

20241028

PMC11509018

10.3390/ijms252011184

39456965