1. The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C
- Author
-
Ho, AK, Wagstaff, JL, Manna, PT, Wartosch, L, Qamar, S, Garman, EF, Freund, SMV, and Roberts, RC
- Subjects
Lipopolysaccharide-induced tumour necrosis factor-α factor ,Endosomes ,Charcot-Marie-Tooth disease ,3. Good health ,Neuropathy - 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.