scholarly journals Structure and function of E3 ubiquitin ligase mindbomb RING domain

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Robert D Wardlow ◽  
Sung Hee Choi ◽  
Brian McMillan ◽  
Stephen C Blacklow
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Structure And Function ◽  
Ring Domain ◽  
And Function

scholarly journals Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
B.E. Riley ◽  
J.C. Lougheed ◽  
K. Callaway ◽  
M. Velasquez ◽  
E. Brecht ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Structure And Function ◽  
And Function

scholarly journals TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Esther L. Jones ◽  
Stephen M. Laidlaw ◽  
Lynn B. Dustin
Keyword(s):  
Innate Immunity ◽  
Ubiquitin Ligase ◽  
Lupus Erythematosus ◽  
Cell Cycle Regulation ◽  
E3 Ubiquitin Ligase ◽  
Structure And Function ◽  
Intracellular Protein ◽  
Systemic Lupus ◽  
And Function ◽  
Cycle Regulation

TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It is also an autoantibody target in Sjögren’s syndrome, systemic lupus erythematosus, and other rheumatic autoimmune diseases. Here, we summarise the structure and function of this enzyme, its roles in innate immunity, adaptive immunity and cellular homeostasis, the pathogenesis of autoimmunity against TRIM21, and the potential impacts of autoantibodies to this intracellular protein.

scholarly journals Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1

Open Biology ◽  
2014 ◽  
Vol 4 (3) ◽  
pp. 130172 ◽  
Author(s):  
Barbara Franke ◽  
Alexander Gasch ◽  
Dayté Rodriguez ◽  
Mohamed Chami ◽  
Muzamil M. Khan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Quaternary Structure ◽  
E3 Ubiquitin Ligase ◽  
Coiled Coil ◽  
Trim Protein ◽  
Muscle Catabolism ◽  
And Function ◽  
Helical Region ◽  
Structural Significance

MuRF1 is an E3 ubiquitin ligase central to muscle catabolism. It belongs to the TRIM protein family characterized by a tripartite fold of RING, B-box and coiled-coil (CC) motifs, followed by variable C-terminal domains. The CC motif is hypothesized to be responsible for domain organization in the fold as well as for high-order assembly into functional entities. But data on CC from this family that can clarify the structural significance of this motif are scarce. We have characterized the helical region from MuRF1 and show that, contrary to expectations, its CC domain assembles unproductively, being the B2- and COS-boxes in the fold (respectively flanking the CC) that promote a native quaternary structure. In particular, the C-terminal COS-box seemingly forms an α-hairpin that packs against the CC, influencing its dimerization. This shows that a C-terminal variable domain can be tightly integrated within the conserved TRIM fold to modulate its structure and function. Furthermore, data from transfected muscle show that in MuRF1 the COS-box mediates the in vivo targeting of sarcoskeletal structures and points to the pharmacological relevance of the COS domain for treating MuRF1-mediated muscle atrophy.

scholarly journals BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes

2018 ◽  
Vol 115 (6) ◽  
pp. 1316-1321 ◽  
Author(s):  
Mikaela D. Stewart ◽  
Elena Zelin ◽  
Abhinav Dhall ◽  
Tom Walsh ◽  
Esha Upadhyay ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Transcriptional Repression ◽  
Suppressor Gene ◽  
Ring Domain ◽  
Estrogen Metabolism ◽  
Missense Mutations ◽  
Histone H2a ◽  
Increased Risk ◽  
Binding Residues ◽  
And Function

Missense mutations that disrupt the RING domain of the tumor suppressor gene BRCA1 lead to increased risk of breast and ovarian cancer. The BRCA1 RING domain is a ubiquitin ligase, whose structure and function rely critically on forming a heterodimer with BARD1, which also harbors a RING domain. The function of the BARD1 RING domain is unknown. In families severely affected with breast cancer, we identified inherited BARD1 missense mutations Cys53Trp, Cys71Tyr, and Cys83Arg that alter three zinc-binding residues of the BARD1 RING domain. Each of these mutant BARD1 proteins retained the ability to form heterodimeric complexes with BRCA1 to make an active ubiquitin ligase, but the mutant BRCA1/BARD1 complexes were deficient in binding to nucleosomes and in ubiquitylating histone H2A. The BARD1 mutations also caused loss of transcriptional repression of BRCA1-regulated estrogen metabolism genes CYP1A1 and CYP3A4; breast epithelial cells edited to create heterozygous loss of BARD1 showed significantly higher expression of CYP1A1 and CYP3A4. Reintroduction of wild-type BARD1 into these cells restored CYP1A1 and CYP3A4 transcription to normal levels, but introduction of the cancer-predisposing BARD1 RING mutants failed to do so. These results indicate that an intact BARD1 RING domain is critical to BRCA1/BARD1 binding to nucleosomes and hence to ubiquitylation of histone H2A and also critical to transcriptional repression of BRCA1-regulated genes active in estrogen metabolism.

scholarly journals The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades  doublecortin proteins to constrain neuronal dendritogenesis

2020 ◽  
pp. jbc.RA120.016210
Author(s):  
Jianing Song ◽  
Ronald A. Merrill ◽  
Andrew Y. Usachev ◽  
Stefan Strack
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
Ubiquitin Ligase ◽  
Hippocampal Neurons ◽  
E3 Ubiquitin Ligase ◽  
Gene Mutations ◽  
Disease Protein ◽  
Associated Proteins ◽  
Interaction Regions ◽  
And Function

Proper brain development and function requires finely controlled mechanisms for protein turnover and disruption of genes involved in proteostasis is a common cause of neurodevelopmental disorders. Kelch-like 15 (KLHL15) is a substrate adaptor for cullin3 (Cul3)-containing E3 ubiquitin ligases and KLHL15 gene mutations were recently described as a cause of severe X-linked intellectual disability (XLID). Here, we used a bioinformatics approach to identify a family of neuronal microtubule-associated proteins (MAPs) as KLHL15 substrates, which are themselves critical for early brain development. We biochemically validated doublecortin (DCX), also an X-linked disease protein, and doublecortin-like kinase 1 and 2 (DCLK1/2) as bona fide KLHL15 interactors and mapped KLHL15 interaction regions to their tandem DCX domains. Shared with two previously identified KLHL15 substrates, a FRY tripeptide at the C-terminal edge of the second DCX domain is necessary for KLHL15-mediated ubiquitination of DCX and DCLK1/2 and subsequent proteasomal degradation. Conversely, silencing endogenous KLHL15 markedly stabilizes these DCX domain-containing proteins and prolongs their half-life. Functionally, overexpression of KLHL15 in the presence of wild-type DCX reduces dendritic complexity of cultured hippocampal neurons, whereas neurons expressing FRY-mutant DCX are resistant to KLHL15. Collectively, our findings highlight the critical importance of the E3 ubiquitin ligase adaptor KLHL15 in proteostasis of neuronal MAPs and identify a regulatory network important for development of the mammalian nervous system.

scholarly journals An E3 ubiquitin ligase fromNicotiana benthamianatargets the replicase ofBamboo mosaic virusand restricts its replication

2018 ◽  
Author(s):  
I-Hsuan Chen ◽  
Jui-En Chang ◽  
Chen-Yu Wu ◽  
Ying-Ping Huang ◽  
Yau-Huei Hsu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Fluorescent Protein ◽  
Transmembrane Domain ◽  
Tobacco Rattle Virus ◽  
E3 Ubiquitin Ligase ◽  
Infection Process ◽  
Ring Domain ◽  
Virus Induced Gene Silencing ◽  
Ubiquitin E3 Ligase ◽  
Rapid Amplification

AbstractOne upregulated host gene identified previously was found involved in the infection process ofBamboo mosaic virus(BaMV). The full-length cDNA of this gene was cloned by 5′- and 3′-rapid amplification of cDNA ends and found to encode a polypeptide containing a conserved RING-domain and a transmembrane domain. The gene might function as an E3 ubiquitin ligase. We designated this protein inNicotiana benthamianaas ubiquitin E3 ligase containing RING-domain 1 (NbUbE3R1). Further characterization by usingTobacco rattle virus-based virus-induced gene silencing revealed an increased BaMV accumulation in both knockdown plants and protoplasts. To further inspect the functional role of NbUbE3R1 in BaMV accumulation, NbUbE3R1 was expressed inN. benthamianaplants. The wild-type NbUbE3R1-orange fluorescent protein (NbUbE3R1-OFP), NbUbE3R1/△TM-OFP (removal of the transmembrane domain) and NbUbE3R1/mRING-OFP (mutation at the RING domain, the E2 interaction site) were transiently expressed in plants. NbUbE3R1 and its derivatives all functioned in restricting BaMV accumulation. The common feature of these constructs was the intact substrate-interacting domain. Yeast two-hybrid and co-immunoprecipitation experiments used to determine the possible viral-encoded substrate of NbUbE3R1 revealed the replicase of BaMV as the possible substrate. In conclusion, we identified an upregulated gene, NbUbE3R1, that plays a role in BaMV replication.

scholarly journals Structure and function of the yeast U-box-containing ubiquitin ligase Ufd2p

2007 ◽  
Vol 104 (40) ◽  
pp. 15599-15606 ◽  
Author(s):  
D. Tu ◽  
W. Li ◽  
Y. Ye ◽  
A. T. Brunger
Keyword(s):  
Ubiquitin Ligase ◽  
Structure And Function ◽  
And Function

scholarly journals Zinc Binding Properties of Engineered RING Finger Domain of Arkadia E3 Ubiquitin Ligase

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Christos T. Chasapis ◽  
Ariadni K. Loutsidou ◽  
Malvina G. Orkoula ◽  
Georgios A. Spyroulias
Keyword(s):  
Ubiquitin Ligase ◽  
Structural Integrity ◽  
Recombinant Expression ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Ring Domain ◽  
Site Directed Mutagenesis ◽  
Zinc Binding ◽  
Ring Finger Domain ◽  
C Terminus

Human Arkadia is a nuclear protein consisted of 989 amino acid residues, with a characteristic RING domain in its C-terminus. The RING domain harbours the E3 ubiquitin ligase activity needed by Arkadia to ubiquitinate its substrates such as negative regulators of TGF- signaling. The RING finger domain of Arkadia is a RING-H2 type and its structure and stability is strongly dependent on the presence of two bound Zn(II) ions attached to the protein frame through a defined Cys3-His2-Cys3 motif. In the present paper we transform the RING-H2 type of Arkadia finger domain to nonnative RING sequence, substituting the zinc-binding residues or to Arginine, through site-directed mutagenesis. The recombinant expression, inEscherichia coli, of the mutants C955R and H960R reveal significant lower yield in respect with the native polypeptide of Arkadia RING-H2 finger domain. In particular, only the C955R mutant exhibits expression yield sufficient for recombinant protein isolation and preliminary studies. Atomic absorption measurements and preliminary NMR data analysis reveal that the C955R point mutation in the RING Finger domain of Arkadia diminishes dramatically the zinc binding affinity, leading to the breakdown of the global structural integrity of the RING construct.

scholarly journals Noncanonical E2 Variant-Independent Function of UBC13 in Promoting Checkpoint Protein Assembly

2008 ◽  
Vol 28 (19) ◽  
pp. 6104-6112 ◽  
Author(s):  
Michael S. Y. Huen ◽  
Jun Huang ◽  
Jingsong Yuan ◽  
Masahiro Yamamoto ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Protein Assembly ◽  
Ring Domain ◽  
Dna Breaks ◽  
Focus Formation ◽  
Checkpoint Protein ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Conjugating Enzyme

ABSTRACT The E2 ubiquitin-conjugating enzyme UBC13 plays pivotal roles in diverse biological processes. Recent studies have elucidated that UBC13, in concert with the E3 ubiquitin ligase RNF8, propagates the DNA damage signal via a ubiquitylation-dependent signaling pathway. However, mechanistically how UBC13 mediates its role in promoting checkpoint protein assembly and its genetic requirement for E2 variants remain elusive. Here we provide evidence to support the idea that the E3 ubiquitin ligase complex RNF8-UBC13 functions independently of E2 variants and is sufficient in facilitating ubiquitin conjugations and accumulation of DNA damage mediator 53BP1 at DNA breaks. The RNF8 RING domain serves as the molecular platform to anchor UBC13 at the damaged chromatin, where localized ubiquitylation events allow sustained accumulation of checkpoint proteins. Intriguingly, we found that only a group of RING domains derived from E3 ubiquitin ligases, which have been shown to interact with UBC13, enabled UBC13-mediated FK2 and 53BP1 focus formation at DNA breaks. We propose that the RNF8 RING domain selects and loads a subset of UBC13 molecules, distinct from those that exist as heterodimers, onto sites of double-strand breaks, which facilitates the amplification of DNA damage signals.

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