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The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C
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 evolutiona...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142333/ https://www.ncbi.nlm.nih.gov/pubmed/27927196 http://dx.doi.org/10.1186/s12915-016-0332-8 |
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author | Ho, Anita K. Wagstaff, Jane L. Manna, Paul T. Wartosch, Lena Qamar, Seema Garman, Elspeth F. Freund, Stefan M. V. Roberts, Rhys C. |
author_facet | Ho, Anita K. Wagstaff, Jane L. Manna, Paul T. Wartosch, Lena Qamar, Seema Garman, Elspeth F. Freund, Stefan M. V. Roberts, Rhys C. |
author_sort | Ho, Anita K. |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-016-0332-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5142333 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-51423332016-12-15 The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C Ho, Anita K. Wagstaff, Jane L. Manna, Paul T. Wartosch, Lena Qamar, Seema Garman, Elspeth F. Freund, Stefan M. V. Roberts, Rhys C. BMC Biol Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12915-016-0332-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-12-07 /pmc/articles/PMC5142333/ /pubmed/27927196 http://dx.doi.org/10.1186/s12915-016-0332-8 Text en © Ho et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Ho, Anita K. Wagstaff, Jane L. Manna, Paul T. Wartosch, Lena Qamar, Seema Garman, Elspeth F. Freund, Stefan M. V. Roberts, Rhys C. The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title_full | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title_fullStr | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title_full_unstemmed | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title_short | The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C |
title_sort | topology, structure and pe interaction of litaf underpin a charcot-marie-tooth disease type 1c |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142333/ https://www.ncbi.nlm.nih.gov/pubmed/27927196 http://dx.doi.org/10.1186/s12915-016-0332-8 |
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