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  • The EMBO Journal (2008) 27, 2018 - 2029
  • doi:10.1038/emboj.2008.123

Published online: 26 June 2008

Implementing the LIM code: the structural basis for cell type-specific assembly of LIM-homeodomain complexes

Mugdha Bhati1,a, Christopher Lee1,a, Amy L Nancarrow1, Mihwa Lee1, Vanessa J Craig1, Ingolf Bach2, J Mitchell Guss1, Joel P Mackay1 and Jacqueline M Matthews1

  1. School of Molecular and Microbial Biosciences, The University of Sydney, New South Wales, Australia
  2. Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

Correspondence to:

Jacqueline M Matthews, School of Molecular and Microbial Biosciences, The University of Sydney, Darlinghurst, New South Wales 2006, Australia. Tel.: +61 2 9351 6025; Fax: +61 2 9351 4726; E-mail: j.matthews@usyd.edu.au

aThese authors contributed equally to this work

Received 16 March 2008; Accepted 2 June 2008

LIM-homeodomain (LIM-HD) transcription factors form a combinatorial 'LIM code' that contributes to the specification of cell types. In the ventral spinal cord, the binary LIM homeobox protein 3 (Lhx3)/LIM domain-binding protein 1 (Ldb1) complex specifies the formation of V2 interneurons. The additional expression of islet-1 (Isl1) in adjacent cells instead specifies the formation of motor neurons through assembly of a ternary complex in which Isl1 contacts both Lhx3 and Ldb1, displacing Lhx3 as the binding partner of Ldb1. However, little is known about how this molecular switch occurs. Here, we have identified the 30-residue Lhx3-binding domain on Isl1 (Isl1LBD). Although the LIM interaction domain of Ldb1 (Ldb1LID) and Isl1LBD share low levels of sequence homology, X-ray and NMR structures reveal that they bind Lhx3 in an identical manner, that is, Isl1LBD mimics Ldb1LID. These data provide a structural basis for the formation of cell type-specific protein–protein interactions in which unstructured linear motifs with diverse sequences compete to bind protein partners. The resulting alternate protein complexes can target different genes to regulate key biological events.

  • Keywords:

    • cell specification,
    • competitive binding,
    • LIM code,
    • LIM homeodomain proteins,
    • protein complexes