Structure of the second phosphoubiquitin–binding site in parkin

Fakih, Rayan; Sauvé, Véronique; Gehring, Kalle

doi:10.1016/j.jbc.2022.102114

Cited by 15 publications

(34 citation statements)

References 51 publications

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“…1 & 2). In contrast to previous reports 29,31 , pUb/pNEDD8 do not bind to the RING0 pocket (Fig. 2 & Extended Data Fig.…”

Section: Discussioncontrasting

confidence: 99%

“…In contrast to the findings from previous studies 29,31 , our data suggest that the two pockets (RING0 and RING1) on Parkin specifically recognize pUbl and pUb/pNEDD8. Although the sequence comparison in Fig.…”

Section: Mechanism Of Specific Interaction Between Parkin and Publ Or...contrasting

confidence: 99%

“…The disease mutation K211N (on RING0), which leads to the loss of pUb-mediated Parkin activation 23,31 , was an interesting phenomenon from a therapeutic perspective. Recently, a group suggested that pUb binds to the RING0 pocket and proposed a new feedforward mechanism of Parkin activation independent of pUbl 29,31 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent publications have suggested two pUb binding sites on Parkin, one in the RING1 pocket and the other in the RING0 pocket 29,31 . The latter suggests a promiscuous nature of interactions between Parkin and phosphorylated ubiquitin-like proteins/domain.…”

Section: Introductionmentioning

confidence: 99%

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Intricate mechanism (s) of substrate specificity and loss of function on disease mutation (K211N) of Parkin

Lenka,

Chaurasiya,

Kumar

2023

Preprint

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Parkin mutations lead to the early onset of Parkinson’s disease. PINK1-mediated phosphorylation of its substrates Ubiquitin (Ub)-like proteins (NEDD8, Ubiquitin) and Ubiquitin-like (Ubl) domain activate autoinhibited Parkin. Substrate specificity on Parkin and the cause of loss of function in disease mutation K211N remain elusive. Herein, we determine the first crystal structure of human Parkin bound with phospho(p)-NEDD8 and establish the mechanism of substrate specificity on Parkin. RING0 pocket is specific for pUbl and does not bind with pUb/pNEDD8. In contrast, pNEDD8 has evolved to bind robustly in the RING1 pocket and shows higher activation of Parkin compared to pUb. Also, the binding of activators in the RING1 and RING0 pockets of Parkin leads to a distinct extent of RING2 displacement during Parkin activation. Furthermore, the crystal structure of pNEDD8-bound Parkin K211N reveals novel conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without losing pNEDD8/pUb binding. This study would help design small-molecule Parkin activators against Parkinson’s disease.

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“…1 & 2). In contrast to previous reports 29,31 , pUb/pNEDD8 do not bind to the RING0 pocket (Fig. 2 & Extended Data Fig.…”

Section: Discussioncontrasting

confidence: 99%

Section: Mechanism Of Specific Interaction Between Parkin and Publ Or...contrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intricate mechanism (s) of substrate specificity and loss of function on disease mutation (K211N) of Parkin

Lenka,

Chaurasiya,

Kumar

2023

Preprint

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show abstract

“…3, 4, 5). A similar a nity was also observed in a recent publication using a truncated construct expressing the R0RB domain of parkin 35 . Our data shows that RING2 and REP displacement after parkin phosphorylation is transient in nature; RING2 and REP return to their original position after the removal of the pUbl (Fig.…”

Section: Discussionsupporting

confidence: 84%

A new feedforward mechanism of Parkin activation

Lenka,

Dahe,

Sahoo

et al. 2023

Preprint

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Parkin E3-ligase is an auto-inhibited enzyme activated by phosphorylation of ubiquitin or ubiquitin-like (Ubl) domain of parkin by PINK1. Parkin mutations are known to affect its function leading to the onset of Parkinson’s disease. Herein, we show a competitive binding mode of the phospho-Ubl and RING2 domains on the RING0 domain, which regulates parkin activity. We show that phosphorylated parkin forms complex with native parkin leading to the activation of autoinhibited parkin in trans. Furthermore, we show that the activator element (ACT) of parkin is required to maintain the enzyme’s kinetics, and removal of ACT slows the enzyme catalysis. We also show that ACT can activate parkin in trans; however, it is more effective when present in the cis molecule. Furthermore, we identified and characterized a new donor ubiquitin binding pocket that plays a crucial role in parkin function.

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PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants

Clausen,

Okarmus,

Voutsinos

et al. 2024

Cell. Mol. Life Sci.

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Parkinson’s disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.

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Structure of the second phosphoubiquitin–binding site in parkin

Cited by 15 publications

References 51 publications

Intricate mechanism (s) of substrate specificity and loss of function on disease mutation (K211N) of Parkin

Intricate mechanism (s) of substrate specificity and loss of function on disease mutation (K211N) of Parkin

A new feedforward mechanism of Parkin activation

PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants

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