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

Bhati, Mugdha, Lee, Christopher, Gadd, Morgan S., Jeffries, Cy M., Kwan, , Ann, Whitten, Andrew E., Trewhella, Jill, Mackay, Joel P. and Matthews, Jacqueline 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: . doi:10.1371/journal.pone.0040719


Author Bhati, Mugdha
Lee, Christopher
Gadd, Morgan S.
Jeffries, Cy M.
Kwan, , Ann
Whitten, Andrew E.
Trewhella, Jill
Mackay, Joel P.
Matthews, Jacqueline M.
Title Solution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactions
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-07-25
Sub-type Article (original research)
DOI 10.1371/journal.pone.0040719
Open Access Status DOI
Volume 7
Issue 7
Total pages 9
Place of publication San Francisco, United States
Publisher blic Library of Science
Subject 1100 Agricultural and Biological Sciences
1300 Biochemistry, Genetics and Molecular Biology
2700 Medicine
Abstract Lhx3 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Article e40719.

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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