scholarly journals IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis

2008 ◽  
Vol 10 (11) ◽  
pp. 1309-1317 ◽  
Author(s):  
Mads Gyrd-Hansen ◽  
Maurice Darding ◽  
Maria Miasari ◽  
Massimo M. Santoro ◽  
Lars Zender ◽  
...  
Keyword(s):  
Cell Survival ◽  
Binding Domain ◽  
Evolutionarily Conserved ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain

2019 ◽  
Vol 21 (6) ◽  
pp. 731-742 ◽  
Author(s):  
Apostolos Polykratis ◽  
Arne Martens ◽  
Remzi Onur Eren ◽  
Yoshitaka Shirasaki ◽  
Mai Yamagishi ◽  
...  
Keyword(s):  
Binding Domain ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals CoCUN, a Novel Ubiquitin Binding Domain Identified in N4BP1

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 284 ◽  
Author(s):  
Ridvan Nepravishta ◽  
Federica Ferrentino ◽  
Walter Mandaliti ◽  
Anna Mattioni ◽  
Janine Weber ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Structural Model ◽  
Functional Characterization ◽  
Binding Domain ◽  
15N Nmr ◽  
Protein Sequence Analysis ◽  
Hydrophobic Patch ◽  
Binding Domains ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

Ubiquitin binding domains (UBDs) are modular elements that bind non-covalently to ubiquitin and act as downstream effectors and amplifiers of the ubiquitination signal. With few exceptions, UBDs recognize the hydrophobic path centered on Ile44, including residues Leu8, Ile44, His68, and Val70. A variety of different orientations, which can be attributed to specific contacts between each UBD and surface residues surrounding the hydrophobic patch, specify how each class of UBD specifically contacts ubiquitin. Here, we describe the structural model of a novel ubiquitin-binding domain that we identified in NEDD4 binding protein 1 (N4BP1). By performing protein sequence analysis, mutagenesis, and nuclear magnetic resonance (NMR) spectroscopy of the 15N isotopically labeled protein, we demonstrate that a Phe-Pro motif in N4BP1 recognizes the canonical hydrophobic patch of ubiquitin. This recognition mode resembles the molecular mechanism evolved in the coupling of ubiquitin conjugation to endoplasmic-reticulum (ER) degradation (CUE) domain family, where an invariant proline, usually following a phenylalanine, is required for ubiquitin binding. Interestingly, this novel UBD, which is not evolutionary related to CUE domains, shares a 40% identity and 47% similarity with cullin binding domain associating with NEDD8 (CUBAN), a protein module that also recognizes the ubiquitin-like NEDD8. Based on these features, we dubbed the region spanning the C-terminal 50 residues of N4BP1 the CoCUN domain, for Cousin of CUBAN. By performing circular dichroism and 15N NMR chemical shift perturbation of N4BP1 in complex with ubiquitin, we demonstrate that the CoCUN domain lacks the NEDD8 binding properties observed in CUBAN. We also show that, in addition to mediating the interaction with ubiquitin and ubiquitinated substrates, both CUBAN and CoCUN are poly-ubiquitinated in cells. The structural and the functional characterization of this novel UBD can contribute to a deeper understanding of the molecular mechanisms governing N4BP1 function, providing at the same time a valuable tool for clarifying how the discrimination between ubiquitin and the highly related NEDD8 is achieved.

scholarly journals Role of the ubiquitin-binding domain of Polη in Rad18-independent translesion DNA synthesis in human cell extracts

2010 ◽  
Vol 38 (19) ◽  
pp. 6456-6465 ◽  
Author(s):  
Valérie Schmutz ◽  
Régine Janel-Bintz ◽  
Jérôme Wagner ◽  
Denis Biard ◽  
Naoko Shiomi ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Human Cell ◽  
Binding Domain ◽  
Translesion Dna Synthesis ◽  
Cell Extracts ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Translesion Dna

scholarly journals A Ubiquitin-Binding Domain in Cockayne Syndrome B Required for Transcription-Coupled Nucleotide Excision Repair

2010 ◽  
Vol 38 (5) ◽  
pp. 637-648 ◽  
Author(s):  
Roy Anindya ◽  
Pierre-Olivier Mari ◽  
Ulrik Kristensen ◽  
Hanneke Kool ◽  
Giuseppina Giglia-Mari ◽  
...  
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Binding Domain ◽  
Nucleotide Excision ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals The Zinc Finger of NEMO Is a Functional Ubiquitin-binding Domain

2008 ◽  
Vol 284 (5) ◽  
pp. 2902-2907 ◽  
Author(s):  
Florence Cordier ◽  
Olivera Grubisha ◽  
François Traincard ◽  
Michel Véron ◽  
Muriel Delepierre ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Binding Domain ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals K29-Selective Ubiquitin Binding Domain Reveals Structural Basis of Specificity and Heterotypic Nature of K29 Polyubiquitin

2015 ◽  
Vol 58 (1) ◽  
pp. 83-94 ◽  
Author(s):  
Yosua Adi Kristariyanto ◽  
Syed Arif Abdul Rehman ◽  
David G. Campbell ◽  
Nicholas A. Morrice ◽  
Clare Johnson ◽  
...  
Keyword(s):  
Binding Domain ◽  
Structural Basis ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zinc Finger ◽  
Proteasome Inhibitors ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

AbstractHDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

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