Solution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactions

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dc.contributor.authorBhati, Men_AU
dc.contributor.authorLee, Cen_AU
dc.contributor.authorGadd, MSen_AU
dc.contributor.authorJeffries, CMen_AU
dc.contributor.authorKwan, AHen_AU
dc.contributor.authorWhitten, AEen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.contributor.authorMackay, JPen_AU
dc.contributor.authorMatthews, JMen_AU
dc.date.accessioned2014-05-05T05:19:08Zen_AU
dc.date.available2014-05-05T05:19:08Zen_AU
dc.date.issued2012-07-25en_AU
dc.date.statistics2014-05-05en_AU
dc.description.abstractLhx3 is a LIM-homeodomain (LIM-HD) transcription factor that regulates neural cell subtype specification and pituitary development in vertebrates, and mutations in this protein cause combined pituitary hormone deficiency syndrome (CPHDS). The recently published structures of Lhx3 in complex with each of two key protein partners, Isl1 and Ldb1, provide an opportunity to understand the effect of mutations and posttranslational modifications on key protein-protein interactions. Here, we use small-angle X-ray scattering of an Ldb1-Lhx3 complex to confirm that in solution the protein is well represented by our previously determined NMR structure as an ensemble of conformers each comprising two well-defined halves (each made up of LIM domain from Lhx3 and the corresponding binding motif in Ldb1) with some flexibility between the two halves. NMR analysis of an Lhx3 mutant that causes CPHDS, Lhx3(Y114C), shows that the mutation does not alter the zinc-ligation properties of Lhx3, but appears to cause a structural rearrangement of the hydrophobic core of the LIM2 domain of Lhx3 that destabilises the domain and/or reduces the affinity of Lhx3 for both Ldb1 and Isl1. Thus the mutation would affect the formation of Lhx3-containing transcription factor complexes, particularly in the pituitary gland where these complexes are required for the production of multiple pituitary cell types and hormones. © 2012 Bhati et al.en_AU
dc.identifier.articlenumbere40719en_AU
dc.identifier.citationBhati, M., Lee, C., Gadd, M. S., Jeffries, C. M., Kwan, A., Whitten, A. E., Trewhella, J., Mackay, J. P., & Matthews, J. M. (2012). Solution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactions. PLoS ONE, 7(7), e40719. doi:10.1371/journal.pone.0040719en_AU
dc.identifier.govdoc4612en_AU
dc.identifier.issn1932-6203en_AU
dc.identifier.issue7en_AU
dc.identifier.journaltitlePLoS ONEen_AU
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0040719en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/5541en_AU
dc.identifier.volume7en_AU
dc.language.isoenen_AU
dc.publisherPublic Libary of Scienceen_AU
dc.subjectHormonesen_AU
dc.subjectNeutronsen_AU
dc.subjectGenesen_AU
dc.subjectProteinsen_AU
dc.subjectSpecificationsen_AU
dc.subjectScatteringen_AU
dc.titleSolution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactionsen_AU
dc.typeJournal Articleen_AU
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