دورية أكاديمية
Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization
| العنوان: | Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization |
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| المؤلفون: | Pathak, Pragya, Alexander, Krista K, Helton, Leah G, Kentros, Michalis, LeClair, Timothy J, Zhang, Xiaojuan, Ho, Franz Y, Moore, Timothy T, Hall, Scotty, Guaitoli, Giambattista, Gloeckner, Christian Johannes, Kortholt, Arjan, Rideout, Hardy, Kennedy, Eileen J |
| المصدر: | Pathak , P , Alexander , K K , Helton , L G , Kentros , M , LeClair , T J , Zhang , X , Ho , F Y , Moore , T T , Hall , S , Guaitoli , G , Gloeckner , C J , Kortholt , A , Rideout , H & Kennedy , E J 2023 , ' Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization ' , ACS chemical neuroscience , vol. 14 , no. 11 , 00259 , pp. 1971-1980 . https://doi.org/10.1021/acschemneuro.3c00259Test |
| سنة النشر: | 2023 |
| المجموعة: | University of Groningen research database |
| الوصف: | Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://research.rug.nl/en/publications/8b0f169c-49a7-4d9a-a76d-669929bf4f40Test |
| DOI: | 10.1021/acschemneuro.3c00259 |
| الإتاحة: | https://doi.org/10.1021/acschemneuro.3c00259Test https://hdl.handle.net/11370/8b0f169c-49a7-4d9a-a76d-669929bf4f40Test https://research.rug.nl/en/publications/8b0f169c-49a7-4d9a-a76d-669929bf4f40Test https://pure.rug.nl/ws/files/689526179/acschemneuro.3c00259.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.7CE9CED0 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acschemneuro.3c00259 |
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