Key Points
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The LIM domain is a modular protein-binding interface that is found in a wide variety of eukaryotic proteins with diverse biological functions.
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The LIM domain can be identified by a conserved sequence: C(X)2C(X)16–23(H/C)X2,4(C/H/E)(X)2C(X)2C(X)14–21(C/H)(X)2/1/3(C/H/D/E)X. Text that is not bold denotes infrequently observed patterns (which are seen in <10% of cases). The conserved residues are zinc-binding ligands that establish a double zinc-finger structure, X denotes any amino acid.
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The LIM domain can bind a wide variety of protein targets. The coordination of zinc provides the LIM domain with a stable framework, whereas the variable portions of the LIM sequence allow for tailoring of high-affinity binding to many structurally and functionally different protein partners.
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LIM proteins function in a diverse collection of biological processes, the unifying themes of which are the control of gene expression and cytoskeletal function.
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The molecular function of LIM domains and LIM proteins is dependent upon the binding of target proteins. Through binding, LIM domains can function as adaptors, competitors, autoinhibitors or localizers. Often, they carry out combinations of these functions.
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An increasing number of LIM proteins has been observed in both the nuclear and the cytoskeletal compartments. An emerging area of investigation is the potential for such proteins to communicate information between these compartments, regulating gene expression to affect cytoskeletal dynamics, and vice versa.
Abstract
First described 15 years ago as a cysteine-rich sequence that was common to a small group of homeodomain transcription factors, the LIM domain is now recognized as a tandem zinc-finger structure that functions as a modular protein-binding interface. LIM domains are present in many proteins that have diverse cellular roles as regulators of gene expression, cytoarchitecture, cell adhesion, cell motility and signal transduction. An emerging theme is that LIM proteins might function as biosensors that mediate communication between the cytosolic and the nuclear compartments.
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Acknowledgements
The authors would like to thank M. Ranall and P. Renfranz for critical reading of the manuscript, and H. Schubert for assistance with the illustration of the three-dimensional protein structures. We are also grateful to J. Matthews for sharing structural data in advance of publication. This work was supported by the Huntsman Cancer Foundation and National Institutes of Health grants to M.C.B.
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Glossary
- HOMEODOMAIN TRANSCRIPTION FACTORS
-
Transcription factors that are crucial for development, and that possess conserved, 60-amino-acid DNA-binding domains.
- SH2 DOMAIN
-
(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.
- SH3 DOMAIN
-
(Src-homology-3 domain). A protein sequence of 50 amino acids that recognizes and binds amino-acid sequences rich in proline.
- LD MOTIF
-
A short sequence found within proteins that has the consensus sequence LDXLLXXL and functions as a protein-binding interface.
- PDZ DOMAIN
-
A protein-interaction domain that often occurs in scaffolding proteins, and is named after the founding members of this protein family (PSD95, Discs large and ZO-1).
- RUBREDOXIN-TYPE ZINC KNUCKLES
-
A tight-turn structure within proteins formed by coordination of a metal ion by two closely spaced cysteine residues in the primary sequence. Rubredoxin is a small iron-sulphur protein whose structure was among the first to be solved by X-ray crystallography.
- GATA-TYPE TRANSCRIPTION FACTORS
-
A family of transcription factors that contain a zinc-finger motif that was first identified in the vertebrate GATA1 protein. These transcription factors bind the consensus sequence GATA in the regulatory regions of genes.
- WD MOTIF
-
A repeat of ∼40 amino acids with a characteristic central tryptophan–aspartic-acid motif that can recognize and bind protein targets containing phosphorylated threonine.
- RING DOMAIN
-
A cysteine-rich tandem zinc-finger domain of 40–60 amino acids often found in E3 ubiquitin ligases.
- PHD
-
The plant homeodomain (PHD) zinc finger is found in many nuclear proteins that are thought to be involved in chromatin-mediated transcriptional regulation.
- FYVE
-
A zinc-finger-containing protein motif that binds the membrane lipid phosphatidylinositol-3-phosphate. The protein that contains FYVE is thereby targeted to the membrane.
- NMR CHEMICAL SHIFT ANALYSIS
-
Changes in the NMR signature of a protein that are induced on addition of an NMR silent binding partner. Amino-acid residues that participate in binding have altered chemical shifts.
- Arp2/3 COMPLEX
-
A complex that consists of two actin-related proteins ARP2 and ARP3, along with five smaller proteins. When activated, the ARP2/3 complex binds to the side of an existing actin filament and nucleates the assembly of a new actin filament. The resulting branch structure is Y-shaped.
- STRESS FIBRE
-
An axial bundle of F-actin and myosin that traverses the cytoplasm. The formation of stress fibres is typically induced by the activity of the GTPase RhoA.
- MEMBRANE RUFFLES
-
Processes that are formed by the movement of lamellipodia in the dynamic process of folding back onto the cell body from which they have extended.
- CARDIOMYOPATHY
-
A disease of the heart muscle.
- Z-LINE
-
A region at the boundaries of muscle sarcomeres in which the actin filaments are anchored. It appears as a dark transverse line in electron micrographs.
- SARCOMERE
-
The basic structural and functional contractile unit of muscle, composed of actin and myosin.
- GROWTH CONE
-
Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.
- MONOOXYGENASE DOMAIN
-
A protein domain that catalyses oxidoreduction reactions using a flavin cofactor.
- CALPONIN-HOMOLOGY DOMAIN
-
A protein domain, often found tandemly arrayed, that functions in the binding of actin.
- RHO FAMILY GTPases
-
Ras-related small GTPases involved in controlling the polymerization of actin.
- NEBULIN SUPER-REPEATS
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A 35-residue motif, found in a uniform repeating pattern along the length of the sequence of nebulin. The motif has a role in binding and stabilizing F-actin.
- MYOFIBRIL
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The structural unit of striated muscle fibres. Several myofibrils make up each fibre.
- SARCOLEMMA
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The plasma membrane (plasmalemma) of a muscle cell.
- SCHWANN CELLS
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Cells that produce the myelin sheath around axons in the peripheral nervous system.
- INTERNEURONS
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Small neurons within the central nervous system that function as connectors between two neurons.
- E-BOX DNA
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DNA in the regulatory regions of genes with the sequence CAGATG, specifically recognized by basic helix–loop–helix transcription factors.
- SERUM-RESPONSE FACTOR
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(SRF). A MADS-domain-containing transcription factor that binds to the serum-response element in the promoter-enhancer region of many genes.
- PROTEASOME
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A protein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.
- E3 UBIQUITIN PROTEIN LIGASE
-
The third enzyme in a series responsible for ubiquitylation and subsequent degradation of target proteins. E3 enzymes, which are numerous, provide platforms for binding target substrates, thereby conferring specificity to this process.
- PLANAR POLARITY
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The pattern of organization of cells within the plane of an epithelium.
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Kadrmas, J., Beckerle, M. The LIM domain: from the cytoskeleton to the nucleus. Nat Rev Mol Cell Biol 5, 920–931 (2004). https://doi.org/10.1038/nrm1499
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DOI: https://doi.org/10.1038/nrm1499
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