7US1

Structure of parkin (R0RB) bound to two phospho-ubiquitin molecules

Summary for 7US1

• Entry DOI: 10.2210/pdb7us1/pdb
• Descriptor: E3 ubiquitin-protein ligase parkin, Ubiquitin-G76 deletion, ZINC ION, ... (6 entities in total)
• Functional Keywords: parkin r0rb, r0rb:2pub, r0rb:pub, ligase
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 3
• Total formula weight: 44238.45

Authors

Fakih, R.,Sauve, V.,Gehring, K. (deposition date: 2022-04-22, release date: 2022-06-22, Last modification date: 2024-11-13)

Primary citation

Fakih, R.,Sauve, V.,Gehring, K.
Structure of the second phosphoubiquitin-binding site in parkin.
J.Biol.Chem., 298:102114-102114, 2022

PubMed Abstract: Parkin and PINK1 regulate a mitochondrial quality control system that is mutated in some early onset forms of Parkinson's disease. Parkin is an E3 ubiquitin ligase and regulated by the mitochondrial kinase PINK1 via a two-step cascade. PINK1 first phosphorylates ubiquitin, which binds a recruitment site on parkin to localize parkin to damaged mitochondria. In the second step, PINK1 phosphorylates parkin on its ubiquitin-like domain (Ubl), which binds a regulatory site to release ubiquitin ligase activity. Recently, an alternative feed-forward mechanism was identified that bypasses the need for parkin phosphorylation through the binding of a second phosphoubiquitin (pUb) molecule. Here, we report the structure of parkin activated through this feed-forward mechanism. The crystal structure of parkin with pUb bound to both the recruitment and regulatory sites reveals the molecular basis for differences in specificity and affinity of the two sites. We use isothermal titration calorimetry measurements to reveal cooperativity between the two binding sites and the role of linker residues for pUbl binding to the regulatory site. The observation of flexibility in the process of parkin activation offers hope for the future design of small molecules for the treatment of Parkinson's disease.

PubMed: 35690145
DOI: 10.1016/j.jbc.2022.102114

Experimental method

X-RAY DIFFRACTION (2.484 Å)