Molecular glue modulates mitochondria

Access through your institution Buy or subscribe Early-onset Parkinson’s disease (EOPD) is a movement disorder caused by loss of specific neurons in the midbrain that are responsible for

fine motor control. Mutations in the ubiquitin ligase parkin and the kinase PINK1 (which work together to target degradation of damaged mitochondria) cause EOPD, as mitochondrial homeostasis

is crucial for neuronal survival. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane, where it phosphorylates ubiquitin and ubiquitin-like (Ubl) domains.

Phospho-ubiquitin (pUb) then recruits parkin to the outer mitochondrial membrane where parkin is phosphorylated. This leads to the damaged organelle being targeted for degradation. Mutations

in the Ubl domain of parkin can reduce PINK1-mediated activation. Compounds that can activate parkin without the need for Ubl are therefore sought after for treatment of EOPD. Now, Sauvé et

al. have shown that a small molecule allosteric modulator can act as a molecular glue to enhance the ability of pUb to activate parkin. The small molecule (called BIO-2007817) works by

gluing pUb (or pUbl) to a zinc-finger domain of parkin called RING0, thus indirectly activating parkin. Further experiments confirmed that BIO-2007817 can trigger autoubiquitination of

unphosphorylated parkin lacking a Ubl, and that presence of pUb was sufficient. Crystal structure studies revealed the binding orientation of BIO-2007817, confirming the mechanism of action.

Finally, in organello ubiquitination and cellular mitophagy assays show how BIO-2007817 can partially rescue pathogenic parkin mutations R42P and V56E, which are associated with EOPD. These

findings could help develop therapeutics for treating EOPD, particularly that caused by mutations affecting PINK1-mediated activation of parkin. This is a preview of subscription content,

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institutional subscriptions * Read our FAQs * Contact customer support AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nature Communications https://www.nature.com/ncomms/ Engi Hassaan Authors

* Engi Hassaan View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Engi Hassaan. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hassaan, E. Molecular glue modulates mitochondria. _Nat Chem Biol_ 20, 1388 (2024). https://doi.org/10.1038/s41589-024-01769-0 Download

citation * Published: 22 October 2024 * Issue Date: November 2024 * DOI: https://doi.org/10.1038/s41589-024-01769-0 SHARE THIS ARTICLE Anyone you share the following link with will be able

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