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PDBsum entry 5c1z
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PDB id:
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Ligase
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Title:
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Parkin (ublr0rbr)
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Structure:
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E3 ubiquitin-protein ligase parkin. Chain: a, b. Synonym: parkin,parkinson juvenile disease protein 2,parkinson disease protein 2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: park2, prkn. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008
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Resolution:
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1.79Å
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R-factor:
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0.193
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R-free:
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0.212
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Authors:
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A.Kumar,J.D.Aguirre,T.E.C.Condos,R.J.Martinez-Torres,V.K.Chaugule, R.Toth,R.Sundaramoorthy,P.Mercier,A.Knebel,D.E.Spratt,K.R.Barber, G.S.Shaw,H.Walden
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Key ref:
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A.Kumar
et al.
(2015).
Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
Embo J,
34,
2506-2521.
PubMed id:
DOI:
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Date:
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15-Jun-15
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Release date:
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29-Jul-15
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PROCHECK
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Headers
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References
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O60260
(PRKN_HUMAN) -
E3 ubiquitin-protein ligase parkin from Homo sapiens
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Seq:
Struc:
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465 a.a.
384 a.a.*
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Key: |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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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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Embo J
34:2506-2521
(2015)
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PubMed id:
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Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
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A.Kumar,
J.D.Aguirre,
T.E.Condos,
R.J.Martinez-Torres,
V.K.Chaugule,
R.Toth,
R.Sundaramoorthy,
P.Mercier,
A.Knebel,
D.E.Spratt,
K.R.Barber,
G.S.Shaw,
H.Walden.
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ABSTRACT
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The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism
(ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family.
Parkin exists in an autoinhibited state that is activated by phosphorylation of
its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We
describe the 1.8 Å crystal structure of human parkin in its fully inhibited
state and identify the key interfaces to maintain parkin inhibition. We identify
the phosphoubiquitin-binding interface, provide a model for the
phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain
primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate
that the addition of phosphoubiquitin leads to displacement of the Ubl domain
through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub
conjugate, thus leading to active parkin. We find the role of the Ubl domain is
to prevent parkin activity in the absence of the phosphorylation signals, and
propose a model for parkin inhibition, optimization for phosphoubiquitin
recruitment, release of inhibition by the Ubl domain and engagement with an
E2~Ub conjugate. Taken together, this model provides a mechanistic framework for
activating parkin.
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Links
