Competition between LIM-binding domains

Abstract

LMO (LIM-only) and LIM-HD (LIM-homeodomain) proteins form a family of proteins that is required for myriad developmental processes and which can contribute to diseases such as T-cell leukaemia and breast cancer. The four LMO and 12 LIM-HD proteins in mammals are expressed in a combinatorial manner in many cell types, forming a transcriptional 'LIM code'. The proteins all contain a pair of closely spaced LIM domains near their N-termini that mediate protein-protein interactions, including binding to the approximately 30-residue LID (LIM interaction domain) of the essential co-factor protein Ldb1 (LIM domain-binding protein 1). In an attempt to understand the molecular mechanisms behind the LIM code, we have determined the molecular basis of binding of LMO and LIM-HD proteins for Ldb1(LID) through a series of structural, mutagenic and biophysical studies. These studies provide an explanation for why Ldb1 binds the LIM domains of the LMO/LIM-HD family, but not LIM domains from other proteins. The LMO/LIM-HD family exhibit a range of affinities for Ldb1, which influences the formation of specific functional complexes within cells. We have also identified an additional LIM interaction domain in one of the LIM-HD proteins, Isl1. Despite low sequence similarity to Ldb1(LID), this domain binds another LIM-HD protein, Lhx3, in an identical manner to Ldb1(LID). Through our and other studies, it is emerging that the multiple layers of competitive binding involving LMO and LIM-HD proteins and their partner proteins contribute significantly to cell fate specification and development.

Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex

“…As previously seen for LMO4, this explains why LDB1 can interact with different LMO and LIM homeodomain proteins. 60 On the other hand, specific side-chain interactions are also necessary to orient the LIM domains and to drive higher-affinity binding. For example, insertion of the LID residue R360 deeply into a pocket of negative charges formed by LMO2 residues contrasts the much smaller negative patch found in the equivalent position on LMO4.…”

Evolutionary, Physicochemical, and Functional Mechanisms of Protein Homooligomerization

“…Another example is the LIM-domain-binding protein Ldb1, a nuclear adaptor protein which interacts with diverse proteins containing LIM domains and plays essential roles in development and cellular differentiation. 20,21 Humans have two close paralogs Ldb1 and Ldb2. Since the loss of Ldb1 causes severe developmental defects in embryos that are not compensated for by Ldb2, Ldb1 and Lbd2 are likely to participate in different pathways.…”

Molecular Recognition of the Tes LIM2–3 Domains by the Actin-related Protein Arp7A

“…Nevertheless, the 1–65 Arp7A -LIM2–3 Tes interaction is reminiscent of the LID Isl1 ·LIM1–2 Lhx3 , LID ldb1 ·LIM1–2 LMO4 , and LID ldb1 ·LIM1–2 LMO2 complexes (46–48). These binary complexes contain tandem LIM domains from members of the LMO and LIM-HD subgroup of LIM domain proteins bound to a LIM-interacting domain (LID) from a partner protein (Isl1 or Ldb1) (46–48). As observed for Arp7A, these tandem LIM domain ligands bind in an antiparallel orientation and engage each LIM domain apolar pocket, suggesting that pocket occupancy is a common feature of tandem LIM domain ligands (Fig.…”