Structural basis for partial redundancy in a class of transcription factors, the LIM homeodomain proteins, in neural cell type specification.
Combinations of LIM homeodomain proteins form a transcriptional "LIM code" to direct the specification of neural cell types. Two paralogous pairs of LIM homeodomain proteins, LIM homeobox protein 3/4 (Lhx3/Lhx4) and Islet-1/2 (Isl1/Isl2), are expressed in developing ventral motor neurons. Lhx3 and Isl1 interact within a well characterized transcriptional complex that triggers motor neuron development, but it was not known whether Lhx4 and Isl2 could participate in equivalent complexes. We have identified an Lhx3-binding domain (LBD) in Isl2 based on sequence homology with the Isl1(LBD) and show that both Isl2(LBD) and Isl1(LBD) can bind each of Lhx3 and Lhx4. X-ray crystal- and small-angle x-ray scattering-derived solution structures of an Lhx4·Isl2 complex exhibit many similarities with that of Lhx3·Isl1; however, structural differences supported by mutagenic studies reveal differences in the mechanisms of binding. Differences in binding have implications for the mode of exchange of protein partners in transcriptional complexes and indicate a divergence in functions of Lhx3/4 and Isl1/2. The formation of weaker Lhx·Isl complexes would likely be masked by the availability of the other Lhx·Isl complexes in postmitotic motor neurons.
School of Molecular Bioscience, The University of Sydney, New South Wales 2006, Australia.
Morgan S
MS
Gadd
Mugdha
M
Bhati
Cy M
CM
Jeffries
David B
DB
Langley
Jill
J
Trewhella
J Mitchell
JM
Guss
Jacqueline M
JM
Matthews
D000818:Animals; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D060588:LIM Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; C558561:Isl2 protein, mouse; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; C102084:Ldb1 protein, mouse; C094898:Lhx3 protein; C108538:Lhx4 protein, mouse; D011994:Recombinant Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1