دورية أكاديمية
أعرض في EDS

MeCP2_E1 N-terminal modifications affect its degradation rate and are disrupted by the Ala2Val Rett mutation.

التفاصيل البيبلوغرافية
العنوان: MeCP2_E1 N-terminal modifications affect its degradation rate and are disrupted by the Ala2Val Rett mutation.
المؤلفون: Sheikh TI; Molecular Neuropsychiatry & Development (MiND) Lab, Brain Science Division, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada., de Paz AM; Department of Biochemistry and Microbiology, University of Victoria, BC V8P 5C2, Canada., Akhtar S; University of Engineering and Technology Taxila, Taxila, Punjab 47080, Pakistan., Ausió J; Department of Biochemistry and Microbiology, University of Victoria, BC V8P 5C2, Canada., Vincent JB; Molecular Neuropsychiatry & Development (MiND) Lab, Brain Science Division, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
المصدر: Human molecular genetics [Hum Mol Genet] 2017 Nov 01; Vol. 26 (21), pp. 4132-4141.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
مواضيع طبية MeSH: Methyl-CpG-Binding Protein 2/*genetics , Methyl-CpG-Binding Protein 2/*metabolism, Alternative Splicing ; Amino Acid Sequence ; Animals ; Cell Line ; Exons ; HEK293 Cells ; Humans ; Mice ; Mutation ; Mutation, Missense ; Protein Isoforms ; Protein Processing, Post-Translational ; Proteolysis ; RNA, Messenger/genetics ; Rett Syndrome/genetics ; Signal Transduction
مستخلص: Methyl CpG-binding protein 2 (MeCP2), the mutated protein in Rett syndrome (RTT), is a crucial chromatin-modifying and gene-regulatory protein that has two main isoforms (MeCP2_E1 and MeCP2_ E2) due to the alternative splicing and switching between translation start codons in exons one and two. Functionally, these two isoforms appear to be virtually identical; however, evidence suggests that only MeCP2_E1 is relevant to RTT, including a single RTT missense mutation in exon 1, Ala2Val. Here, we show that N-terminal co- and post-translational modifications differ for MeCP2_E1 and MeCP2_E1-Ala2Val, which result in different protein degradation rates in vitro. We report complete N-methionine excision (NME) for MeCP2_E1 and evidence of excision of multiple alanine residues from the N-terminal polyalanine stretch. For MeCP2_E1-Ala2Val, we observed only partial NME and N-acetylation (NA) of either methionine or valine. The localization of MeCP2_E1 and co-localization with chromatin appear to be unaffected by the Ala2Val mutation. However, a higher proteasomal degradation rate was observed for MeCP2_E1-Ala2Val compared with that for wild type MeCP2_E1. Thus, the etiopathology of Ala2Val is likely due to a reduced bio-availability of MeCP2 because of the faster degradation rate of the unmodified defective protein. Our data on the effects of the Ala2Val mutation on N-terminal modifications of MeCP2 may be applicable to Ala2Val mutations in other disease genes for which no etiopathological mechanism has been established.
(© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
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معلومات مُعتمدة: MOP -130417 Canada CIHR
المشرفين على المادة: 0 (MECP2 protein, human)
0 (Mecp2 protein, mouse)
0 (Methyl-CpG-Binding Protein 2)
0 (Protein Isoforms)
0 (RNA, Messenger)
تواريخ الأحداث: Date Created: 20171004 Date Completed: 20180321 Latest Revision: 20181113
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5886153
DOI: 10.1093/hmg/ddx300
PMID: 28973632
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2083
DOI:10.1093/hmg/ddx300