LIM-domain-binding protein 1: a multifunctional cofactor that interacts with diverse proteins

Abstract

The ubiquitous nuclear adaptor protein LIM-domain-binding protein 1 (Ldb1) was originally identified as a cofactor for LIM-homeodomain and LIM-only (LMO) proteins that have fundamental roles in development. In parallel, Ldb1 has been shown to have essential functions in diverse biological processes in different organisms. The recent targeting of this gene in mice has revealed roles for Ldb1 in neural patterning and development that have been conserved throughout evolution. Furthermore, the elucidation of the three-dimensional structures of LIM-Ldb1 complexes has provided insight into the molecular basis for the ability of Ldb1 to contact diverse LIM-domain proteins. It has become evident that Ldb1 is a multi-adaptor protein that mediates interactions between different classes of transcription factors and their co-regulators and that the nature of these complexes determines cell fate and differentiation.

Figure 1

Species relationships and domain organization of LIM-domain-binding proteins. (A) Phylogenetic tree constructed from the aligned protein sequences. Nematodes and Drosophila carry one, vertebrates two, and zebrafish four LIM-domain-binding protein (Ldb) genes. (B) Schematic diagram showing domain organization. The dimerization domain (DD), nuclear localization sequence (NLS) and LIM interaction domain (LID) are shown for mouse Ldb1 and Ldb2, Drosophila Ldb/Chip and Caenorhabditis elegans LDB (using the numbering of the Ldb1A splice variant). The other interaction domain (OID, boxed) comprises residues 438–456 in Drosophila Ldb/Chip (Torigoi et al., 2000) and the Ldb1/Chip conserved domain (LLCD, dashed box) comprises residues 201–249 in Ldb1 and 387–426 in Chip (Van Meyel et al., 2003).

Figure 2

The stoichiometry and composition of Ldb1 complexes. (A) Ldb1–LIM-HD tetramers have major roles in cellular development. (B) Incorrect stoichiometry, for example, by overexpression of Ldb1, leads to abnormal development. (C) LMO proteins regulate LIM-HD activity by effectively competing with LIM-HDs for binding to the LID. Overexpression of LMOs can lead to uncontrolled cell proliferation. (D) Other active complexes involve monomeric Ldb1. (E) Cofactor exchange by RLIM can regulate LIM-HD activity. bHLH, basic helix–loop–helix; Ldb1, LIM-domain-binding protein 1; LIM-HD, LIM-homeodomain; LMO, LIM-only protein; Ub, ubiquitin.

Figure 3

Stoichiometry and binding domains of Ldb1–LIM-HD complexes. (A) Ldb1–Lhx3 tetrameric complex in V2 interneuron development. (B) Ldb1–Isl-1–Lhx3 hexameric complexes in motor-neuron development. DD, dimerization domain; HD, homeodomain; Lbd1, LIM domain binding protein 1; LID, LIM interaction domain.

Figure 4

Recognition of LIM domains by Ldb–LID. (A) Structure of a complex formed by LMO4-LIM1 (shown in surface representation) and the Ldb1–LID (in yellow). Side chains involved in electrostatic interactions are red (negative) and blue (positive). Residues in group 1 LIM domains that specify binding to Ldb are magenta. (B) Consensus sequence of the LIM1 domains from group 1 proteins (fully conserved residues are upper case, highly conserved residues are lower case) and the sequence of LIM-kinase are shown. Zinc-binding residues are marked by an asterisk. Boxed residues are coloured as in A. Ldb1, LIM-domain-binding protein 1; LID, LIM interaction domain; LIM-HD, LIM-homeodomain; LMO, LIM-only protein.