Structural basis of generic versus specific E2–RING E3 interactions in protein ubiquitination

Gundogdu, Mehmet; Walden, Helen

doi:10.1002/pro.3690

Cited by 43 publications

(36 citation statements)

References 93 publications

(236 reference statements)

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“…Parkin-mediated ubiquitylation can only take place once Parkin RING1 engages E2 ~ UB and the donor UB is transferred from the E2 catalytic cysteine to Cys431 on Parkin Rcat, termed transthiolation (Section 2) [67]. It has been extensively shown, however, that Parkin exists in a compact, autoinhibited conformation, where the UBL domain exerts an inhibitory effect on both E2 binding and transthiolation [68,69].…”

Section: Regulation Of Parkin By Auto-inhibition and Allosteric Activationmentioning

confidence: 99%

A mechanistic review of Parkin activation

Gundogdu

Tadayon

Salzano

et al. 2021

Biochimica et Biophysica Acta (BBA) - General Subjects

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Parkin and phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) constitute a feed-forward signalling pathway that mediates autophagic removal of damaged mitochondria (mitophagy). With over 130 mutations identified to date in over 1000 patients with early onset parkinsonism, Parkin is considered a hot spot of signalling pathways involved in PD aetiology. Parkin is an E3 ligase and how its activity is regulated has been extensively studied: inter-domain interactions exert a tight inhibition on Parkin activity; binding to phosphoubiquitin relieves this auto-inhibition; and phosphorylation of Parkin shifts the equilibrium towards maximal Parkin activation. This review focusses on recent, structural findings on the regulation of Parkin activity. What follows is a mechanistic introduction to the family of E3 ligases that includes Parkin, followed by a brief description of structural elements unique to Parkin that lock the enzyme in an autoinhibited state, contrasted with emerging models that have shed light on possible mechanisms of Parkin activation.

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Section: Regulation Of Parkin By Auto-inhibition and Allosteric Activationmentioning

confidence: 99%

A mechanistic review of Parkin activation

Gundogdu

Tadayon

Salzano

et al. 2021

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…MuRF1 structure is characterized by a RBCC (RING-B-box-coiled-coil) motif constituted by an N-terminal RING domain (23–79), a MuRF family specific motif (MFC) motif (79–113), a B-box type 2 (Bb2) domain (117–161), a central helical domain (166–328) with a COS-box motif (269–328) and a C-terminal acidic tail (328–353). Several regions have been identified for their interaction with MuRF1 partners (substrates in dark blue and other interactors in light blue): Titin [ 2 ], cardiac troponin I [ 21 , 28 ], muscle-type creatine kinase (MCK) [ 29 ], c-Jun [ 22 ], the ubiquitin conjugating enzymes (UBE2s) [ 30 ], CARP 119–325 [ 31 ]. HD, helical domain.…”

Section: Figurementioning

confidence: 99%

MuRF1/TRIM63, Master Regulator of Muscle Mass

Peris-Moreno

Taillandier

Polge

2020

IJMS

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The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

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“…While in mammals only 2 E1 enzymes for ubiquitin are known, roughly 40 E2 conjugating enzymes and >600 E3 ligases have been identified (Zheng and Shabek, 2017). This implies that E2 enzymes usually support multiple E3 ligases, and a given E2 is likely to be involved in diverse biological processes (Gundogdu and Walden, 2019;Kwon and Ciechanover, 2017). A key missing piece in understanding ubiquitin-regulated positioning of vesicles by the RNF26-associated complex is the contribution of a cognate E2 enzyme.…”

Section: Introductionmentioning

confidence: 99%