Academic Journal
The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C
| العنوان: | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
|---|---|
| المؤلفون: | Ho, AK, Wagstaff, JL, Manna, PT, Wartosch, L, Qamar, S, Garman, EF, Freund, SMV, Roberts, RC |
| بيانات النشر: | BioMed Central //doi.org/10.1186/s12915-016-0332-8 BMC Biology |
| سنة النشر: | 2016 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Charcot-Marie-Tooth disease, Endosomes, Lipopolysaccharide-induced tumour necrosis factor-α factor, Neuropathy |
| الوصف: | BACKGROUND: Mutations in Lipopolysaccharide-induced tumour necrosis factor-α factor (LITAF) cause the autosomal dominant inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 1C (CMT1C). LITAF encodes a 17 kDa protein containing an N-terminal proline-rich region followed by an evolutionarily-conserved C-terminal 'LITAF domain', which contains all reported CMT1C-associated pathogenic mutations. RESULTS: Here, we report the first structural characterisation of LITAF using biochemical, cell biological, biophysical and NMR spectroscopic approaches. Our structural model demonstrates that LITAF is a monotopic zinc-binding membrane protein that embeds into intracellular membranes via a predicted hydrophobic, in-plane, helical anchor located within the LITAF domain. We show that specific residues within the LITAF domain interact with phosphoethanolamine (PE) head groups, and that the introduction of the V144M CMT1C-associated pathogenic mutation leads to protein aggregation in the presence of PE. CONCLUSIONS: In addition to the structural characterisation of LITAF, these data lead us to propose that an aberrant LITAF-PE interaction on the surface of intracellular membranes contributes to the molecular pathogenesis that underlies this currently incurable disease. ; Wellcome-Beit Prize; Intermediate Clinical Fellowship (093809/Z/10/Z); Wellcome Trust Strategic Award 100140; Wellcome Trust grant 093026 |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://www.repository.cam.ac.uk/handle/1810/262440 |
| DOI: | 10.17863/CAM.7704 |
| الاتاحة: | https://www.repository.cam.ac.uk/handle/1810/262440 https://doi.org/10.17863/CAM.7704 |
| Rights: | Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.56493A3F |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.7704 |
|---|