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

Authors
  • Ho, Anita K.1
  • Wagstaff, Jane L.2
  • Manna, Paul T.1
  • Wartosch, Lena1
  • Qamar, Seema1
  • Garman, Elspeth F.3
  • Freund, Stefan M. V.2
  • Roberts, Rhys C.1
  • 1 University of Cambridge, Cambridge Biomedical Campus, Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK , Cambridge (United Kingdom)
  • 2 Francis Crick Avenue, Cambridge Biomedical Campus, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK , Cambridge (United Kingdom)
  • 3 University of Oxford, Department of Biochemistry, South Parks Road, Oxford, OX1 3QU, UK , Oxford (United Kingdom)
Type
Published Article
Journal
BMC Biology
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Dec 07, 2016
Volume
14
Issue
1
Identifiers
DOI: 10.1186/s12915-016-0332-8
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundMutations 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.ResultsHere, 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.ConclusionsIn 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.

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