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PDBsum entry 5caw
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Signaling protein
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PDB id
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5caw
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Contents |
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298 a.a.
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76 a.a.
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315 a.a.
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PDB id:
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| Name: |
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Signaling protein
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Title:
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Structure of pediculus humanus parkin bound to phospho-ubiquitin
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Structure:
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E3 ubiquitin-protein ligase parkin. Chain: a, c. Fragment: unp residues 141-461. Engineered: yes. Other_details: covalently modified with phospho-ubiquitin at cys349. Polyubiquitin-b. Chain: b, d. Engineered: yes. Mutation: yes.
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Source:
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Pediculus humanus subsp. Corporis. Body louse. Organism_taxid: 121224. Gene: phum_phum233570. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606.
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Resolution:
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2.62Å
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R-factor:
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0.229
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R-free:
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0.260
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Authors:
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T.Wauer,D.Komander
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Key ref:
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T.Wauer
et al.
(2015).
Mechanism of phospho-ubiquitin-induced PARKIN activation.
Nature,
524,
370-374.
PubMed id:
DOI:
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Date:
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30-Jun-15
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Release date:
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22-Jul-15
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PROCHECK
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Headers
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References
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E0VIU9
(E0VIU9_PEDHC) -
E3 ubiquitin-protein ligase parkin from Pediculus humanus subsp. corporis
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Seq:
Struc:
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461 a.a.
298 a.a.
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Enzyme class:
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Chains A, C:
E.C.2.3.2.31
- RBR-type E3 ubiquitin transferase.
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Reaction:
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[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
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DOI no:
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Nature
524:370-374
(2015)
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PubMed id:
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Mechanism of phospho-ubiquitin-induced PARKIN activation.
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T.Wauer,
M.Simicek,
A.Schubert,
D.Komander.
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ABSTRACT
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The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1
(encoded by PARK6) are mutated in autosomal-recessive juvenile Parkinsonism
(AR-JP) and work together in the disposal of damaged mitochondria by mitophagy.
PINK1 is stabilized on the outside of depolarized mitochondria and
phosphorylates polyubiquitin as well as the PARKIN ubiquitin-like (Ubl) domain.
These phosphorylation events lead to PARKIN recruitment to mitochondria, and
activation by an unknown allosteric mechanism. Here we present the crystal
structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated
ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and
activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate
pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding
leads to straightening of a helix in the RING1 domain, and the resulting
conformational changes release the Ubl domain from the PARKIN core; this
activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl
phosphorylation by PINK1, leading to conformational changes within the Ubl
domain and stabilization of an open, active conformation of PARKIN. We redefine
the role of the Ubl domain not only as an inhibitory but also as an activating
element that is restrained in inactive PARKIN and released by phosphoUb. Our
work opens up new avenues to identify small-molecule PARKIN activators.
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Links
