LIM domains are protein structural domains, composed of two contiguous zinc fingers, separated by a two-amino acid residue hydrophobic linker. The domain name is an acronym of the three genes in which it was first identified (LIN-11, Isl-1 and MEC-3). LIM is a protein interaction domain that is involved in binding to many structurally and functionally diverse partners. The LIM domain appeared in eukaryotes sometime prior to the most recent common ancestor of plants, fungi, amoeba and animals. In animal cells, LIM domain-containing proteins often shuttle between the cell nucleus where they can regulate gene expression, and the cytoplasm where they are usually associated with actin cytoskeletal structures involved in connecting cells together and to the surrounding matrix, such as stress fibers, focal adhesions and adherens junctions.
Discovery LIM domains are named after their initial discovery in the three homeobox proteins that have the following functions:
Lin-11 – asymmetric division of vulvar blast cells Isl-1 – motor neuron development of neuroepithelial cells Mec-3 – differentiation of touch receptor neurons
Sequence and Structure Humans contain 73 described genes encoding different LIM domain-containing proteins. These LIM domains have divergent amino acid sequences apart from certain key residues involved in zinc binding, which facilitate the formation of a stable protein core and tertiary fold. The sequence variation between different LIM domains may be due to the evolution of novel binding sites for diverse partners on top of the conserved stable core. Additionally, LIM domain proteins are functionally diverse; especially during the early evolution of animals, the LIM domain recombined with a variety of other domain types to create these diverse proteins with new functionality. The sequence signature of LIM domains is as follows: [C]-[X]2–4-[C]-[X]13–19-[W]-[H]-[X]2–4-[C]-[F]-[LVI]-[C]-[X]2–4-[C]-[X]13–20-C-[X]2–4-[C] LIM domains frequently occur in multiples, as seen in proteins such as TES, LMO4, and can also be attached to other domains in order to confer a binding or targeting function upon them, such as LIM-kinase.
Roles LIM-domain containing proteins have been shown to play roles in cytoskeletal organization, organ development, regulation of plant cell development, cell lineage specification, and regulation of gene transcription. LIM proteins are also implicated in a variety of heart and muscle conditions, oncogenesis, neurological disorders and other diseases. LIM-domains mediate a variety of protein–protein interactions in many different cellular processes. However a large subset of LIM proteins are recruited to actin cytoskeletal structures that are under a mechanical load. Direct force-activated F-actin binding by LIM recruits LIM domain proteins to stressed cytoskeletal networks and is an example of a mechanosensing mechanism by which cytoskeletal tension governs mechanical homeostasis, nuclear localization, gene expression, and other cellular physiology.
Classification The LIM superclass of genes have been classified into 14 classes: ABLIM, CRP, ENIGMA, EPLIN, LASP, LHX, LMO, LIMK, LMO7, MICAL, PXN, PINCH, TES, and ZYX. Six of these classes (i.e., ABLIM, MICAL, ENIGMA, ZYX, LHX, LM07) originated in the stem lineage of animals, and this expansion is thought to have made a major contribution to the origin of animal multicellularity. Asides lineage of animals, there are an entire class of plant LIM genes that were classified into four different classes: WLIM1, WLIM2, PLIM1, PLIM2, and FLIM (XLIM). These are sorted into 4 different subfamilies: αLIM1, βLIM1, γLIM2, and δLIM2. The αLIM1 subclades include PLIM1, WLIM1, and FLIM (XLIM). βLIM1 is a new subfamily, so no current distinguishable subclades. γLIM2 subclades contain WLIM2 and PLIM2. The final subfamily δLIM2 contains WLIM2, and PLIM2. LIM domains are also found in various bacterial lineages where they are typically fused to a metallopeptidase domain. Some versions show fusions to an inactive P-loop NTPase at their N-terminus and a single transmembrane helix. These domain fusions suggest that the prokaryotic LIM domains are likely to regulate protein processing at the cell membrane. The domain architectural syntax is remarkably parallel to those of the prokaryotic versions of the B-box zinc finger and the AN1 zinc finger domains. LIM domain containing proteins serve many specific functions in cells such as adherens junction, cytoarchitecture, specification of cell polarity, nuclear-cytoplasmic shuttling, and protein trafficking. These domains can be found in eukaryotes, plants, animal, fungi, and mycetozoa. It was classified as A, B, C, and D. These classifications are further sorted into three groups.
Group 1 This group contains LIM domain classes A and B. They are typically fused to other functional domains such as kinases. The subclasses for these domains are LIM-homeodomain transcription factors, LMO proteins, and LIM kinases.
LIM-homeodomain transcription factors They have multifunctionality primarily focusing on development of the nervous system, activation of transcription, and cell fate specification during development. The nervous system relies on the LIM domain type for differentiation of neurotransmitter biosynthetic pathways.
LMO proteins These proteins focus on overall development of multiple cell types as well as oncogenesis and transcriptional regulation. Oncogenesis was found to occur due to the expression of LMO 1 and LMO 2 in T-cell leukemia patients.
LIM kinases The purpose of these proteins is the establishment and regulation of the cytoskeleton. The regulation of the cytoskeleton by these kinases is through phosphorylation of cofilin, which allows for the accumulation of actin filaments. Notably, they have been found to be responsible for regulation of cell motility and morphogenesis.
Group 2 This group contains LIM domain class C, which are localized typically in the cytoplasm. These domains are internally duplicated with two copies per a protein. Also, they are more similar to each than classes A and B.
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