title: The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Ho
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Wagstaff
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Manna
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Lena
authors.initials: L
authors.lastname: Wartosch
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
authors.forename: Seema
authors.initials: S
authors.lastname: Qamar
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: Elspeth F
authors.initials: EF
authors.lastname: Garman
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
authors.forename: Stefan M V
authors.initials: SM
authors.lastname: Freund
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK. rcr20@cam.ac.uk.
authors.forename: Rhys C
authors.initials: RC
authors.lastname: Roberts
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D004983:Ethanolamines / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D066263:Protein Aggregation, Pathological; D011487:Protein Conformation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D004983:Ethanolamines; C118738:LITAF protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C017800:zinc-binding protein; C005448:phosphorylethanolamine
keywords: Charcot-Marie-Tooth disease; Endosomes; Lipopolysaccharide-induced tumour necrosis factor-α factor; Neuropathy