Structure of an E6AP-UbcH7 Complex: Insights into Ubiquitination by the E2-E3 Enzyme Cascade

Huang, Lan; Kinnucan, E.; Wang, Guangli; Beaudenon, Sylvie; Howley, Peter M.; Huibregtse, Jon M.; Pavletich, Nikola P.

doi:10.1126/science.286.5443.1321

Cited by 500 publications

(629 citation statements)

References 38 publications

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“…While these experiments demonstrate a crucial role for Ube3a in synaptic transmission and suggest that the fundamental defect may be in synaptic function, the mechanisms by which Ube3a regulates synaptic function remain to be elucidated. UBE3A encodes a HECT (homologous to the E6-AP carboxyl terminus) domain E3 ubiquitin ligase that catalyzes the addition of ubiquitin to lysine residues on substrate proteins, leading to the degradation of the ubiquitinated substrate protein [52][53][54][55][56][57][58][59]. Human genetic studies have identified several mutations that specifically disrupt the ubiquitin ligase activity of UBE3A while having no effect on protein expression or substrate interactions (Fig.…”

Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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Section: Cellular and Molecular Underpinnings Of Asmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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“…The catalytic cleft between the two lobes of the HECT domain is the site of many of the reported mutations. 49 Screening of the coding region by SSCP followed by direct sequencing is a relatively reliable way of detecting mutations. Frameshift, nonsense, and splice site mutations have been identified.…”

Section: Genetics Of Angelman Syndromementioning

confidence: 99%

Angelman syndrome: a review of clinical and genetic aspects

Laan

Haeringen

Brouwer

1999

Clinical Neurology and Neurosurgery

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“…In recent years, several general principles have emerged for protein-protein interactions in UBL transfer cascades [15][16][17][18][19][20][21][22][23][24][25][26] . Nonetheless, the selective coordination of enzymes within a particular UBL's cascade remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8

Huang

Miller

Mathew

et al. 2004

Nat Struct Mol Biol

130

109

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Ubiquitin-like proteins (UBLs), such as NEDD8, are transferred to their targets by distinct, parallel, multi-enzyme cascades that involve the sequential action of E1, E2, and E3 enzymes. How do enzymes within a particular UBL conjugation cascade interact with each other? We report here that the unique N-terminal sequence of NEDD8's E2, Ubc12, selectively recruits NEDD8's E1 to promote Ubc12~NEDD8 thioester formation. A peptide corresponding to Ubc12's N-terminus (Ubc12N26) specifically binds and inhibits NEDD8's E1, the heterodimeric APPBP1-UBA3 complex. The structure of APPBP1-UBA3-Ubc12N26 reveals conserved Ubc12 residues docking in a groove generated by loops conserved in UBA3s but not other E1s, explaining why this interaction is unique to the NEDD8 pathway. These studies define a novel mechanism for E1-E2 interaction and show how enzymes within a particular UBL conjugation cascade can be tethered together by unique protein-protein interactions emanating from their common structural scaffolds.

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Structure of an E6AP-UbcH7 Complex: Insights into Ubiquitination by the E2-E3 Enzyme Cascade

Cited by 500 publications

References 38 publications

Angelman Syndrome

Angelman Syndrome

Angelman syndrome: a review of clinical and genetic aspects

A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8

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