A Structural Basis for the Regulation of the LIM-Homeodomain Protein Islet 1 (Isl1) by Intra- and Intermolecular Interactions

Gadd, M.S.; Jacques, D.A.; Nisevic, Ivan; Craig, Vanessa J.; Kwan, Ann H.; Guss, J. Mitchell; Matthews, Jacqueline M.

doi:10.1074/jbc.m113.478586

Cited by 22 publications

(25 citation statements)

References 64 publications

(72 reference statements)

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“…In humans, LHX3 is broadly expressed in many tissues, including the pancreas. Although this particular transcription factor has not been previously reported to affect insulin secretory pathways, it does interact with several other transcription factors including insulin gene enhancer protein ISL1 and LIM homeobox transcription factor 1-alpha (LMX1A), which are known regulators of insulin gene expression [26].…”

Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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Aims/hypothesis Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND). Methods DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed. Results Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10 −5 ). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10 −5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10 ) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways. Conclusions/interpretation Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.

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Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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“…The isolated LIM domains from these proteins tend to aggregate but can be stabilized by tethering the LIM domains to a LID, allowing their interaction to form soluble complexes. The thermofluor experiments are expected to report differences in folding and binding as LID sequences that bind more tightly should result in higher apparent melting point ( T m ) values, but only complexes that contain the same globular domain were compared to control for contributions of domain stability. These data indicated that the WT ISL2 binds LHX3/4 more tightly than does the mutant R282G, ~2°C higher T m for LHX4 and ~3°C for LHX3 (Supporting Information Figure S2A).…”

Section: Resultsmentioning

confidence: 99%

“…For thermofluor experiments, purified LIM–LID fusion proteins were dialyzed (overnight at 4°C) into the same reservoir of 20 mM Tris (pH 8.0), 150 mM NaCl, 1 mM TCEP, and experiments carried out as described in Ref. with samples at 0.6 mg/mL protein. FRET‐based dilution experiments with 3C‐protease treated mYPet–LID–LIM 1 + 2 ‐mECFP fusion proteins were conducted as described previously, over the protein concentration range of 1‐9 μM.…”

Section: Methodsmentioning

confidence: 99%

Mutation in a flexible linker modulates binding affinity for modular complexes

et al. 2019

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Tandem beta zippers are modular complexes formed between repeated linear motifs and tandemly arrayed domains of partner proteins in which β‐strands form upon binding. Studies of such complexes, formed by LIM domain proteins and linear motifs in their intrinsically disordered partners, revealed spacer regions between the linear motifs that are relatively flexible but may affect the overall orientation of the binding modules. We demonstrate that mutation of a solvent exposed side chain in the spacer region of an LHX4–ISL2 complex has no significant effect on the structure of the complex, but decreases binding affinity, apparently by increasing flexibility of the linker.

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“…However, Lim domains can also function as a protein-binding interface (36,89,(112)(113)(114)(115). The high-resolution structures of some of the Lim domains have been determined using nuclear magnetic resonance and X-ray crystallography, which suggests that the Lim domain zinc finger consists of two antiparallel β-hairpins with a short α-helix (78)(79)(80)82,(116)(117)(118)(119). The conserved cysteine/histidine/aspartate residues coordinate with the zinc atom which helps to maintain the secondary and tertiary structure of the Lim domains (28) (as depicted in Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

Siddiqui

Badmalia

Patel

2020

Preprint

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Lim domains are one of the most abundant types of zinc-finger domains and are linked with diverse cellular functions ranging from cytoskeleton maintenance to gene regulation. Zyxin family Lim domains perform the critical cellular functions and are indispensable for cellular integrity. Despite having these important functions the fundamental nature of the sequence, structure, functions, and interactions of the Zyxin family Lim domains are largely unknown. Therefore, we have used a set ofin-silicotools and bioinformatics databases to distill the fundamental properties of the Zyxin family proteins/Lim domains from their amino acid sequence, phylogeny, biochemical analysis, post-translational modifications, structure-dynamics, molecular interactions, and functions. Consensus analysis of the nuclear export signal suggests a conserved Leucine-rich motif composed of LxxLxL/LxxxLxL. Molecular modeling and structural analysis demonstrate that Lim domains of the members of the Zyxin family proteins share similarities with transcriptional regulators, suggesting they could interact with nucleic acids as well. Normal mode, Covariance, and Elastic Network Model analysis of Zyxin family Lim domains suggest only the Lim1 region has similar internal dynamics properties, compared to Lim2/3. Protein expression/mutational frequency studies of the Zyxin family demonstrated higher expression and mutational frequency rates in various malignancies. Protein-protein interactions indicate that these proteins could facilitate metabolic rewiring and oncogenic addiction paradigm. Our comprehensive analysis of the Zyxin family proteins indicates that the Lim domains function in a variety of ways and could be implicated in rational protein engineering and might lead as a better therapeutic target for various diseases, including cancers.

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A Structural Basis for the Regulation of the LIM-Homeodomain Protein Islet 1 (Isl1) by Intra- and Intermolecular Interactions

Cited by 22 publications

References 64 publications

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Mutation in a flexible linker modulates binding affinity for modular complexes

Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

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