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From Proteopedia
UBE3A isoform 2 AZUL domain
Structural highlights
DiseaseUBE3A_HUMAN Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:105830; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.[1] [2] FunctionUBE3A_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.[3] [4] [5] [6] [7] [8] Publication Abstract from PubMedAbnormalities in the expression of the ubiquitin ligase UBE3A (ubiquitin-protein ligase E3A)/E6AP (human papillomavirus E6-associated protein) are implicated in neurological disorders including Angelman syndrome and autism. Human UBE3A is expressed as three protein isoforms that differ in their abundance and subcellular localization. While previous studies indicate isoform-specific functions, the distinct roles of each isoform in human development remain unknown. The isoforms differ only by an extension at the N-terminal end of the AZUL (N-terminal zinc [Zn]-binding domain Amino-terminal Zn finger of the UBE3A Ligase) domain, which tethers UBE3A to the proteasome by interaction with proteasomal subunit Rpn10. Differences in the structure and biophysical properties of UBE3A isoforms likely contribute to their individual functions. Here, we use a combination of NMR spectroscopy and other biophysical and biochemical techniques to identify differences in structure, dynamics, and the Rpn10 binding of the AZUL isoforms. We show that the AZUL domain structure is retained in all three isoforms with an extended N-terminal helix in longer isoforms 2 and 3. Accordingly, all isoforms could effectively associate with the Rpn10. Significant differences between the isoforms were found in their propensities to multimerize where only the longer isoforms 2 and 3 of the AZUL domain could form dimers, which may play a role in the previously observed oligomerization-dependent activation of the UBE3A. Moreover, our NMR relaxation dispersion experiments revealed a dynamic Zn-coordination site in isoforms 1 and 3, but not in isoform 2 of UBE3A, suggesting its possible isoform-specific sensitivity to oxidative stress. This structural and biophysical characterization of the isoforms will advance our understanding of isoform-specific functions of UBE3A and may contribute to future treatment strategies for Angelman syndrome and other UBE3A-related diseases. Differences in structure, dynamics, and zinc coordination between isoforms of human ubiquitin ligase UBE3A.,Bregnard TA, Fairchild D, Chen X, Erlandsen H, Tarasov SG, Walters KJ, Korzhnev DM, Bezsonova I J Biol Chem. 2024 Dec 30;301(2):108149. doi: 10.1016/j.jbc.2024.108149. PMID:39742997[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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