Molecular glue modulates mitochondria

Nature

Molecular glue modulates mitochondria"


Play all audios:

Loading...

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,


access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99


/ 30 days cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on


SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about


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


to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing


initiative


Trending News

Chris packham blasts the chase stars for swimming with dolphins

Chris said: “I've met the Chasers, they're a really nice bunch of people, but they're not natural histori...

Cristiano ronaldo: juventus star sent off on champions league debut

Ronaldo signed for Juventus from Real Madrid in July for £105million, with the Serie A giants hopeful he can propel them...

Neobank n26 gives customers in france local iban numbers

THE GERMAN BANK HOPES MONEY TRANSFERS WILL BECOME EASIER - BUT IT WILL CHANGE HOW CUSTOMERS DECLARE THEIR ACCOUNT ON TAX...

Javascript support required...

Mansoor, rush debate without daigle - newport beach news

A clear divergence of beliefs piled up between Assemblyman Allan Mansoor, a Republican from Costa Mesa, and political ne...

Latests News

Molecular glue modulates mitochondria

Access through your institution Buy or subscribe Early-onset Parkinson’s disease (EOPD) is a movement disorder caused by...

Can you earn a dy-no-mite score on our quiz?

Memorial Day Sale! Join AARP for just $11 per year with a 5-year membership Join now and get a FREE gift. Expires 6/4  G...

Instant money transfers now possible between french banks with just a phone number

‘WERO’ LAUNCHED IN FRANCE IN OCTOBER AND STATES TRANSFERS WILL TAKE ONLY 10 SECONDS The instant money transfer app Wero ...

Competition launched for aspiring photographers to capture godiva festival

Godiva Festival is set to bring back the photography competition for a lucky person to join the festival's official...

What support is there available for recruiting volunteers?

England Hockey has guidance and information on this site here.  You may also be interested in the Sport England ClubMatt...

Top