A structural basis for the regulation of the LIM-homeodomain protein islet 1 (Isl1) by intra- and intermolecular interactions.

Gadd, Morgan Stuart and Jacques, David A and Nisevic, Ivan and Craig, Vanessa J and Kwan, Ann H and Guss, J Mitchell and Matthews, Jacqueline M (2013) A structural basis for the regulation of the LIM-homeodomain protein islet 1 (Isl1) by intra- and intermolecular interactions. Journal of Biological Chemistry, 228. pp. 21924-21935. ISSN 0021-9258

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Abstract

Islet 1 (Isl1) is a transcription factor of the LIM-homeodomain (LIM-HD) protein family and is essential for many developmental processes. LIM-HD proteins all contain two protein-interacting LIM domains, a DNA-binding homeodomain (HD), and a C-terminal region. In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3. The LIM domains of Isl1 have been implicated in inhibition of DNA binding potentially through an intramolecular interaction with or close to the HD. Here we investigate the LBD as a candidate intramolecular interaction domain. Competitive yeast-two hybrid experiments indicate that the LIM domains and LBD from Isl1 can interact with apparently low affinity, consistent with no detection of an intermolecular interaction in the same system. Nuclear magnetic resonance studies show that the interaction is specific, whereas substitution of the LBD with peptides of the same amino acid composition but different sequence is not specific. We solved the crystal structure of a similar but higher affinity complex between the LIM domains of Isl1 and the LIM interaction domain from the LIM-HD cofactor protein LIM domain-binding protein 1 (Ldb1) and used these coordinates to generate a homology model of the intramolecular interaction that indicates poorer complementarity for the weak intramolecular interaction. The intramolecular interaction in Isl1 may provide protection against aggregation, minimize unproductive DNA binding, and facilitate cofactor exchange within the cell.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Biological Chemistry
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1312
Subjects:
ID Code:
89277
Deposited By:
Deposited On:
15 Dec 2017 15:18
Refereed?:
Yes
Published?:
Published
Last Modified:
11 Feb 2020 03:49