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

Mutations in Lipopolysaccharide-induced tumour necrosis factor-? 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.
Mesh Terms:
Amino Acid Sequence, Carrier Proteins, Cell Line, Charcot-Marie-Tooth Disease, Ethanolamines, HeLa Cells, Humans, Membrane Proteins, Mutation, Nuclear Proteins, Protein Aggregation, Pathological, Protein Conformation, Transcription Factors
BMC Biol
Date: Dec. 07, 2015
Download Curated Data For This Publication
233242
Switch View:
  • Interactions 1