scholarly journals Synthesis and delivery of a stable phosphorylated ubiquitin probe to study ubiquitin conjugation in mitophagy

2021 ◽  
Vol 57 (74) ◽  
pp. 9438-9441
Author(s):  
Guy Mann ◽  
Gandhesiri Satish ◽  
Prasad Sulkshane ◽  
Shaswati Mandal ◽  
Michael H. Glickman ◽  
...  
Keyword(s):  
E3 Ligase ◽  
Ubiquitin Conjugation

Synthesis, delivery and cellular conjugation analysis of differentially phosphorylated ubiquitin probes by parkin E3 ligase during mitophagy.

scholarly journals Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation

2018 ◽  
Author(s):  
Tara E.C. Condos ◽  
Karen M. Dunkerley ◽  
E. Aisha Freeman ◽  
Kathryn R. Barber ◽  
Jacob D. Aguirre ◽  
...  
Keyword(s):  
Binding Site ◽  
Weak Interaction ◽  
Molecular Pathology ◽  
Early Onset ◽  
E3 Ligase ◽  
Unresolved Question ◽  
C Terminus ◽  
Catalytic Cysteine ◽  
Ubiquitin Conjugation ◽  
Early Onset Parkinson’S Disease

ABSTRACTThe mechanism of activation and ubiquitin conjugation by the E3 ligase parkin is pivotal to understand the molecular pathology of early-onset Parkinson’s disease. Parkin is normally autoinhibited but is activated by the kinase PINK1 that phosphorylates parkin’s N-terminal ubiquitin-like (pUbl) domain and ubiquitin. How these alter the structure of parkin to allow recruitment of an E2~Ub conjugate to enhance ubiquitination is an unresolved question. We present the structure of an incoming E2~Ub conjugate with the phospho-ubiquitin bound C-terminus of parkin (R0RBR). We show the UbcH7~Ub conjugate is recruited by R0RBR parkin in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR experiments indicate there is re-modelling near the RING0/RING2 interface remote from the E2-binding site. This, and parkin phosphorylation lead to rapid reactivity of the RING2(Rcat) catalytic cysteine in parkin, needed for ubiquitin transfer. Parkin phosphorylation also leads to relocation and weak interaction of the pUbl domain with the RING0 domain that is enhanced upon E2~Ub recruitment indicating these events act synergistically to drive parkin activity.

scholarly journals Characterization and identification of ubiquitin conjugation sites with E3 ligase recognition specificities

2015 ◽  
Vol 16 (Suppl 1) ◽  
pp. S1 ◽  
Author(s):  
Van-Nui Nguyen ◽  
Kai-Yao Huang ◽  
Chien-Hsun Huang ◽  
Tzu-Hao Chang ◽  
Neil Bretaña ◽  
...  
Keyword(s):  
E3 Ligase ◽  
Ubiquitin Conjugation

scholarly journals Ubiquitination of serine, threonine, or lysine residues on the cytoplasmic tail can induce ERAD of MHC-I by viral E3 ligase mK3

2007 ◽  
Vol 177 (4) ◽  
pp. 613-624 ◽  
Author(s):  
Xiaoli Wang ◽  
Roger A. Herr ◽  
Wei-Jen Chua ◽  
Lonnie Lybarger ◽  
Emmanuel J.H.J. Wiertz ◽  
...  
Keyword(s):  
Complex I ◽  
E3 Ligase ◽  
Mhc I ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Histocompatibility Complex ◽  
Lysine Residues ◽  
Ubiquitin Conjugation ◽  
Infected Cells ◽  
Immune Detection ◽  
Major Histocompatibility Complex I

The mechanism by which substrates for endoplasmic reticulum–associated degradation are retrotranslocated to the cytosol remains largely unknown, although ubiquitination is known to play a key role. The mouse γ-herpesvirus protein mK3 is a viral RING-CH–type E3 ligase that specifically targets nascent major histocompatibility complex I heavy chain (HC) for degradation, thus blocking the immune detection of virus-infected cells. To address the question of how HC is retrotranslocated and what role mK3 ligase plays in this action, we investigated ubiquitin conjugation sites on HC using mutagenesis and biochemistry approaches. In total, our data demonstrate that mK3-mediated ubiquitination can occur via serine, threonine, or lysine residues on the HC tail, each of which is sufficient to induce the rapid degradation of HC. Given that mK3 has numerous cellular and viral homologues, it will be of considerable interest to determine the pervasiveness of this novel mechanism of ubiquitination.

A Caged E3 Ligase Ligand for PROTAC-Mediated Protein Degradation with Light

2019 ◽  
Author(s):  
Cyrille Kounde ◽  
Maria M. Shchepinova ◽  
Edward Tate
Keyword(s):  
Protein Degradation ◽  
Irradiation Time ◽  
E3 Ligase ◽  
Von Hippel Lindau ◽  
Short Irradiation ◽  
Short Irradiation Time ◽  
Spatiotemporal Control

A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.

From Inhibition to Degradation: Targeting the Anti-apoptotic Protein Myeloid Cell Leukemia 1(MCL1)

2019 ◽  
Author(s):  
James Papatzimas ◽  
Evgueni Gorobets ◽  
Ranjan Maity ◽  
Mir Ishruna Muniyat ◽  
Justin L. MacCallum ◽  
...  
Keyword(s):  
Small Molecules ◽  
E3 Ligase ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
New Class ◽  
Apoptotic Protein ◽  
Family Protein ◽  
Ubiquitination Pathway

<div> <div> <div> <p>Here we show the development of heterobifunctional small molecules capable of selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 family protein degraders. </p> </div> </div> </div>

PHOTACs Enable Optical Control of Protein Degradation

2019 ◽  
Author(s):  
Martin Reynders ◽  
Bryan Matsuura ◽  
Marleen Bérouti ◽  
Daniele Simoneschi ◽  
Antonio Marzio ◽  
...  
Keyword(s):  
Protein Degradation ◽  
E3 Ligase ◽  
Optical Control ◽  
Cellular Proteins ◽  
Bifunctional Molecules ◽  
Protein Levels ◽  
Lead Compounds ◽  
Subsequent Degradation ◽  
Temporal And Spatial ◽  
Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

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