SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1.Reportar como inadecuado




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Reference: Jeyabalan, J, Nesbit, MA, Galvanovskis, J et al., (2010). SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1. PloS one, 5 (5), Article: e10646.Citable link to this page:

 

SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1.

Abstract: BACKGROUND: SEDLIN, a 140 amino acid subunit of the Transport Protein Particle (TRAPP) complex, is ubiquitously expressed and interacts with the transcription factors c-myc promoter-binding protein 1 (MBP1), pituitary homeobox 1 (PITX1) and steroidogenic factor 1 (SF1). SEDLIN mutations cause X-linked spondyloepiphyseal dysplasia tarda (SEDT). METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effects of 4 missense (Asp47Tyr, Ser73Leu, Phe83Ser and Val130Asp) and the most C-terminal nonsense (Gln131Stop) SEDT-associated mutations on interactions with MBP1, PITX1 and SF1 by expression in COS7 cells. Wild-type SEDLIN was present in the cytoplasm and nucleus and interacted with MBP1, PITX1 and SF1; the SEDLIN mutations did not alter these subcellular localizations or the interactions. However, SEDLIN was found to homodimerize, and the formation of dimers between wild-type and mutant SEDLIN would mask a loss in these interactions. A mammalian SEDLIN null cell-line is not available, and the interactions between SEDLIN and the transcription factors were therefore investigated in yeast, which does not endogenously express SEDLIN. This revealed that all the SEDT mutations, except Asp47Tyr, lead to a loss of interaction with MBP1, PITX1 and SF1. Three-dimensional modelling studies of SEDLIN revealed that Asp47 resides on the surface whereas all the other mutant residues lie within the hydrophobic core of the protein, and hence are likely to affect the correct folding of SEDLIN and thereby disrupt protein-protein interactions. CONCLUSIONS/SIGNIFICANCE: Our studies demonstrate that SEDLIN is present in the nucleus, forms homodimers and that SEDT-associated mutations cause a loss of interaction with the transcription factors MBP1, PITX1 and SF1.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Oliver Bird Fund   Funder: Arthritis Research Campaign   Funder: European Union   Funder: Medical Research Council   Funder: Nuffield Foundation   Notes:Copyright 2010 Jeyabalan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Bibliographic Details

Publisher: Public Library of Science

Publisher Website: http://www.plos.org

Journal: PloS onesee more from them

Publication Website: http://www.plosone.org

Issue Date: 2010

pages:Article: e10646Identifiers

Urn: uuid:c1245a26-00c8-45f4-bec6-3d4357b27922

Source identifier: 58611

Eissn: 1932-6203

Doi: https://doi.org/10.1371/journal.pone.0010646

Issn: 1932-6203 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: Humans Subcellular Fractions Cell Line Saccharomyces cerevisiae Phosphopyruvate Hydratase Transcription Factors DNA-Binding Proteins Tumor Suppressor Proteins Tumor Markers, Biological Two-Hybrid System Techniques Protein Binding Protein Transport Mutation Paired Box Transcription Factors Mutant Proteins Steroidogenic Factor 1 Protein Multimerization Models, Biological Models, Molecular Membrane Transport Proteins Tiny URL: pubs:58611

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Autor: Jeyabalan, J - institutionUniversity of Oxford fundingThe Nuffield Foundation fundingMedical Research Council fundingOliver Bird

Fuente: https://ora.ox.ac.uk/objects/uuid:c1245a26-00c8-45f4-bec6-3d4357b27922



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