title: 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.
authors.affiliation: School of Molecular and Microbial Biosciences, The University of Sydney, NSW, Australia. j.matthews@usyd.edu.au
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Matthews
authors.forename: Mugdha
authors.initials: M
authors.lastname: Bhati
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Craig
authors.forename: Janet E
authors.initials: JE
authors.lastname: Deane
authors.forename: Cy
authors.initials: C
authors.lastname: Jeffries
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Amy L
authors.initials: AL
authors.lastname: Nancarrow
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009928:Organ Specificity; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D011506:Proteins