scholarly journals Angelman syndrome–associated point mutations in the Zn2+-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome

2018 ◽  
Vol 293 (47) ◽  
pp. 18387-18399 ◽  
Author(s):  
Simone Kühnle ◽  
Gustavo Martínez-Noël ◽  
Flavien Leclere ◽  
Sebastian D. Hayes ◽  
J. Wade Harper ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Angelman Syndrome ◽  
Protein Complexes ◽  
Point Mutations ◽  
Estrogen Receptor Α ◽  
Autism Spectrum ◽  
26S Proteasome ◽  
Interacting Protein ◽  
Functional Defect ◽  
Spectrum Disorders

Deregulation of the HECT ubiquitin ligase UBE3A/E6AP has been implicated in Angelman syndrome as well as autism spectrum disorders. We and others have previously identified the 26S proteasome as one of the major UBE3A-interacting protein complexes. Here, we characterize the interaction of UBE3A and the proteasomal subunit PSMD4 (Rpn10/S5a). We map the interaction to the highly conserved Zn2+-binding N-terminal (AZUL) domain of UBE3A, the integrity of which is crucial for binding to PSMD4. Interestingly, two Angelman syndrome point mutations that affect the AZUL domain show an impaired ability to bind PSMD4. Although not affecting the ubiquitin ligase or the estrogen receptor α–mediated transcriptional regulation activities, these AZUL domain mutations prevent UBE3A from stimulating the Wnt/β-catenin signaling pathway. Taken together, our data indicate that impaired binding to the 26S proteasome and consequential deregulation of Wnt/β-catenin signaling might contribute to the functional defect of these mutants in Angelman syndrome.

scholarly journals E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

2020 ◽  
Vol 21 (22) ◽  
pp. 8515
Author(s):  
Manon Brunet ◽  
Claire Vargas ◽  
Dorian Larrieu ◽  
Jérôme Torrisani ◽  
Marlène Dufresne
Keyword(s):  
Thyroid Hormone ◽  
Ubiquitin Ligase ◽  
Hormone Receptor ◽  
Cell Cycle Progression ◽  
Thyroid Hormone Receptor ◽  
E3 Ubiquitin Ligase ◽  
Autism Spectrum ◽  
Causative Gene ◽  
Interacting Protein ◽  
C Terminus

The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.

scholarly journals Phosphorylation of Estrogen Receptor α at Serine 118 Directs Recruitment of Promoter Complexes and Gene-Specific Transcription

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2517-2526 ◽  
Author(s):  
Tamika T. Duplessis ◽  
Christopher C. Williams ◽  
Steven M. Hill ◽  
Brian G. Rowan
Keyword(s):  
Estrogen Receptor ◽  
Cyclin D1 ◽  
Transcriptional Activation ◽  
Protein Complexes ◽  
Estrogen Receptor Α ◽  
Gene Promoters ◽  
Interacting Protein ◽  
Steroid Receptor Coactivator ◽  
Estrogen Response ◽  
Transcriptional Coregulators

Phosphorylation of estrogen receptor α (ERα) is important for receptor function, although the role of specific ERα phosphorylation sites in ERα-mediated transcription remains to be fully evaluated. Transcriptional activation by ERα involves dynamic, coordinate interactions with coregulators at promoter enhancer elements to effect gene expression. To determine whether ERα phosphorylation affects recruitment of unique protein complexes at gene-specific promoters, changes in ERα Ser118 phosphorylation were assessed for effects on receptor and coregulator recruitment and transcription of ERα-regulated genes. Chromatin immunoprecipitation assays to measure promoter association found a 17β-estradiol (E2)-dependent recruitment of ERα at 150 min to ERα-regulated promoters, whereas ERα phosphorylated at Ser118 was dissociated from promoters after E2 treatment. Mutation of Ser118 to alanine (S118A) altered unliganded and ligand-induced association of ERα and p160 coregulators with ERα target promoters when compared with wild-type (WT)-ERα transfection. S118A and WT-ERα exhibited a similar level of recruitment to the estrogen response element-driven pS2 promoter and induced pS2 mRNA after E2 treatment. Although WT-ERα was recruited to c-myc and cyclin D1 promoters after E2 treatment and induced mRNA expression, S118A exhibited reduced interaction with c-myc and cyclin D1 promoters, and E2 did not induce c-myc and cyclin D1 mRNA. In addition, S118A resulted in increased recruitment of steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and activated in breast cancer-1 to pS2, c-myc, and cyclin D1 irrespective of the presence of E2. Together, these data indicate that site specific phosphorylation of ERα directs gene-specific recruitment of ERα and transcriptional coregulators to ERα target gene promoters.

scholarly journals Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

2019 ◽  
Author(s):  
Gabrielle L. Sell ◽  
Wendy Xin ◽  
Emily K. Cook ◽  
Mark A. Zbinden ◽  
Thomas B. Schaffer ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Angelman Syndrome ◽  
Developmental Disorders ◽  
Motor Coordination ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Altered Expression ◽  
Exciting Potential

ABSTRACTIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

scholarly journals Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish

2021 ◽  
Vol 14 ◽  
Author(s):  
Yasaman Pakdaman ◽  
Elsa Denker ◽  
Eirik Austad ◽  
William H. J. Norton ◽  
Hans O. Rolfsnes ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Ubiquitin Ligase ◽  
Cerebellar Atrophy ◽  
Behavioral Changes ◽  
26S Proteasome ◽  
Spinocerebellar Ataxias ◽  
Interacting Protein ◽  
Ubiquitin Ligase Activity ◽  
Wide Range ◽  
The Brain

The ubiquitin ligase CHIP (C-terminus of Hsc70-interacting protein) is encoded by STUB1 and promotes ubiquitination of misfolded and damaged proteins. CHIP deficiency has been linked to several diseases, and mutations in the human STUB1 gene are associated with recessive and dominant forms of spinocerebellar ataxias (SCAR16/SCA48). Here, we examine the effects of impaired CHIP ubiquitin ligase activity in zebrafish (Danio rerio). We characterized the zebrafish stub1 gene and Chip protein, and generated and characterized a zebrafish mutant causing truncation of the Chip functional U-box domain. Zebrafish stub1 has a high degree of conservation with mammalian orthologs and was detected in a wide range of tissues in adult stages, with highest expression in brain, eggs, and testes. In the brain, stub1 mRNA was predominantly detected in the cerebellum, including the Purkinje cell layer and granular layer. Recombinant wild-type zebrafish Chip showed ubiquitin ligase activity highly comparable to human CHIP, while the mutant Chip protein showed impaired ubiquitination of the Hsc70 substrate and Chip itself. In contrast to SCAR16/SCA48 patients, no gross cerebellar atrophy was evident in mutant fish, however, these fish displayed reduced numbers and sizes of Purkinje cell bodies and abnormal organization of Purkinje cell dendrites. Mutant fish also had decreased total 26S proteasome activity in the brain and showed behavioral changes. In conclusion, truncation of the Chip U-box domain leads to impaired ubiquitin ligase activity and behavioral and anatomical changes in zebrafish, illustrating the potential of zebrafish to study STUB1-mediated diseases.

scholarly journals The structure of Neurexin 1α (n1α) and its role as synaptic organizer

Bionatura ◽  
2019 ◽  
Vol 4 (2) ◽  
pp. 883-886
Author(s):  
Marjorie Zambonino ◽  
Pamela Pereira
Keyword(s):  
Protein Complexes ◽  
Autism Spectrum ◽  
Knock Out ◽  
Adhesion Protein ◽  
Neuropsychiatric Diseases ◽  
Transmission Of Information ◽  
Complex Protein ◽  
Spectrum Disorders ◽  
Knock Out Mice ◽  
The Brain

α - and b-neurexins (NRXNs) are transmembrane adhesion protein complexes localized in presynaptic membranes into neurons and interact with the postsynaptic neuroligins (NLGNs). Our findings indicate that the neurexin 1α (n1α) is a synaptic organizer that directs postsynaptic development in neurons, evidenced in GABAergic neurons and trials with Knock-out Mice. Also, the interactions between hypervariable surfaces of n1α and ligands (neurexophilin, a-dystroglycan, and GABAA) promotes a proper protein-binding recognition, and consequently, a better synaptic adhesion. There is a direct relationship between mental disorders and the n1α assemblage because NRXN1 gene encodes for n1α proteins which are involved in the transmission of information into the brain. For this reason, damage in this complex-protein or some neurexin gene variations causes pathological abnormalities and neuropsychiatric diseases such as schizophrenia, autism spectrum disorders, and intellectual disabilities.

Problem behavior in autism spectrum disorders: A paradigmatic self-organized perspective of network structures

2019 ◽  
Vol 42 ◽  
Author(s):  
Lucio Tonello ◽  
Luca Giacobbi ◽  
Alberto Pettenon ◽  
Alessandro Scuotto ◽  
Massimo Cocchi ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Problem Behaviors ◽  
Autism Spectrum ◽  
The Self ◽  
Network Structures ◽  
Self Organized ◽  
Critical Equilibrium ◽  
Self Organized Criticality ◽  
Acute Agitation ◽  
Spectrum Disorders

AbstractAutism spectrum disorder (ASD) subjects can present temporary behaviors of acute agitation and aggressiveness, named problem behaviors. They have been shown to be consistent with the self-organized criticality (SOC), a model wherein occasionally occurring “catastrophic events” are necessary in order to maintain a self-organized “critical equilibrium.” The SOC can represent the psychopathology network structures and additionally suggests that they can be considered as self-organized systems.

Novel players fine-tune plant trade-offs

2015 ◽  
Vol 58 ◽  
pp. 83-100 ◽  
Author(s):  
Selena Gimenez-Ibanez ◽  
Marta Boter ◽  
Roberto Solano
Keyword(s):  
Ubiquitin Ligase ◽  
Feedback Loop ◽  
Molecular Level ◽  
26S Proteasome ◽  
Signalling Molecules ◽  
Transcriptional Reprogramming ◽  
Trade Offs ◽  
Jaz Proteins ◽  
Regulatory Feedback Loop ◽  
Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

Disfluency Characteristics Observed in Young Children With Autism Spectrum Disorders: A Preliminary Report

2010 ◽  
Vol 20 (2) ◽  
pp. 42-50 ◽  
Author(s):  
Laura W. Plexico ◽  
Julie E. Cleary ◽  
Ashlynn McAlpine ◽  
Allison M. Plumb
Keyword(s):  
Autism Spectrum Disorders ◽  
Young Children ◽  
Children With Autism ◽  
Descriptive Study ◽  
Autism Spectrum ◽  
Typically Developing ◽  
Children With Asd ◽  
Young Children With Autism ◽  
Spectrum Disorders ◽  
Developmental Stuttering

This descriptive study evaluates the speech disfluencies of 8 verbal children between 3 and 5 years of age with autism spectrum disorders (ASD). Speech samples were collected for each child during standardized interactions. Percentage and types of disfluencies observed during speech samples are discussed. Although they did not have a clinical diagnosis of stuttering, all of the young children with ASD in this study produced disfluencies. In addition to stuttering-like disfluencies and other typical disfluencies, the children with ASD also produced atypical disfluencies, which usually are not observed in children with typically developing speech or developmental stuttering. (Yairi & Ambrose, 2005).

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