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The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C

Authors
  • Ho, AK
  • Wagstaff, JL
  • Manna, Paul
  • Wartosch, Lena
  • Qamar, Seema
  • Garman, EF
  • Freund, SMV
  • Roberts, Rhys
Publication Date
Dec 07, 2016
Source
Apollo - University of Cambridge Repository
Keywords
Language
English
License
Green
External links

Abstract

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

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