LINC complex

Last updated December 05, 2024

The linker of nucleoskeleton and cytoskeleton (LINC) complex is a protein complex associated with both inner and outer membranes of the nucleus. It is composed of SUN-domain proteins and KASH-domain proteins. The SUN-domain proteins are membrane-embedded proteins within the inner nuclear membrane (INM). They interact with nuclear lamins, chromatin and an assortment of INM filament and polymer networks within the nucleus. Likewise, KASH domain proteins (called Nesprins in mammals^[1]) are embedded in the outer nuclear membrane (ONM) and interact with the SUN-domain proteins in the perinuclear (lumen) space between the two membranes. This interaction within the nuclear envelope lumen composes higher-order assemblies that are responsible for the transmission of force across the nuclear envelope^[1]. The KASH domain proteins also cross the outer nuclear membrane to interact with actin filaments, microtubule filaments (through dynein and kinesin motors), intermediate filaments (through spectrin), centrosomes and cytoplasmic organelles. The number of SUN-domain and KASH-domain proteins increased in evolution.^[2]

Components

Inner Nuclear Membrane

The Sad-1 and UNC-84 (SUN) domain-containing proteins within the nucleus interact with lamins A, B, C and chromosomes. Within the perinuclear space (between inner and outer nuclear membranes) are SUN-1 and -2 which form connections with the KASH domain proteins on nesprin and the nuclear envelope lumen^[3]. Interestingly, the removal of either SUN -1 or -2 individually will not disrupt LINC complex connectivity, indicating the similarity between the two proteins. Their structure and function may appear to be similar, but not identical; Their mode of binding differentiate them: SUN -1 anchors to the nuclear envelope in the absence of lamin A/C, meanwhile SUN -2 is anchored to the nuclear envelope with help from lamin A/C. Furthermore, SUN -2 has much more involvement within structuring higher-order systems (such as the LINC complex), whereas SUN -1 predominantly interacts with nuclear pore complexes and meiosis^[4].

Outer Nuclear Membrane

The KASH family of proteins is a major component of the LINC complex, totaling six members and ultimately engaging with all aspects of the cytoskeleton. A significant portion of the KASH family are the four nesprin proteins: nesprin -1 (encoded by SYNE1), nesprin -2 (encoded by SYNE2), nesprin -3 (encoded by SYNE3), and nesprin -4 (encoded by SYNE4); The other two KASH family protein members are Jaw1/LRMP (encoded by JAW1) and KASH5 (encoded by KASH5)^[3]. The nesprin family is evolutionarily conserved, signified by the four evolutions of the nesprin protein. The largest of the nesprin proteins at their full length are aptly titled 'giant' nesprin -1 and -2. These two nesprin contain three major domains: the N-terminal domain binds to the actin cytoskeleton through Calponin Homology (CH), the C-terminal KASH domain binds to the nuclear envelope, and a central rod domain with multiple spectrin repeats connects CH and KASH domains for protein-protein interactions^[5].

Function

The function of the LINC complex appears to be in many cell activities. One of the primary features of the LINC Complex is nuclear relocation and orientation. Similarly, the LINC complex is involved with moving meiotic chromosomes to find their homologues at leptotene/zygotene, attaching the centrosome to the outer nuclear membrane, formation of the nuclear pore complex, and responding to extracellular mechanical stimuli. Many of the functions previously listed can be correlated to a cellular response to an external stimulus. LINC complex, by virtue of providing internal cell connectivity, is required for sensing of various mechanical stimuli.

There is an important connection between the integral LINC complex component lamin A/C and chromatin/chromosome expression. While the exact mechanism is not yet fully understood, it is speculated that a dense network of lamin A/C controls the access to heterochromatin and transcription factor localization. This is supported by low lamin A/C concentrations seen in embryonic stem cells while in an open chromatin state. The removal of major LINC complex component nesprin -2 has been observed to alter the localization of integral histones for wound healing, further connecting LINC complex to gene expression and controlling cellular fate^[4].

LINC Complex's Role in Mechanotransduction

Mechanotransduction has been established as the ability of the nucleus to sense mechanical forces which triggers a biological response, converting the initial stimulus into some form of electrochemical activity. This phenomenon can be evoked through a multitude of mechanical pathways, including compression, shear stresses, osmotic changes, cell adhesions, vibrational stimuli and intracellular generated forces. The LINC complex's biggest strength is the existence of the physical connection which links cytoplasmic actin to the lamins of the nucleus. Therefore, signals are capable of transmitting upwards of 12.5 - 25 times faster than what is seen from passive diffusion or molecular-based signaling^[6], thus allowing the nucleus to respond within minutes. Nuclear stiffening is one particular response controlled by LINC complex interaction, which was found to be initiated through the actin-binding nesprin -1 in the cytoskeleton. Stretching nesprin -1 triggers a rapid phosphorylation of emerin, located at the inner nuclear membrane, which alters lamin A and begins a downstream transcription cascade of mechanically regulated genes^[7].

Mechanical forces received by the LINC complex can also impact protein transfer across the nuclear envelope due to the LINC complex's connection with nuclear pore complexes (NPCs). NPCs interact with lamina within the nucleus as well as SUN-1, directly connecting them to the nuclear responses to force transmission. One protein pathway, YAP/TAZ, has been shown to import into the nucleus under nucleus deformation or strain. Similarly, work from the Driscoll laboratory demonstrated that the import of YAP under strain of the nucleus is hindered if the LINC complex is disrupted via knockdown of nesprin -1 giant^[7].

Related Research Articles

The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.

The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is composed of similar proteins in the various organisms. It is composed of three main components: microfilaments, intermediate filaments, and microtubules, and these are all capable of rapid growth and or disassembly depending on the cell's requirements.

The nucleoplasm, also known as karyoplasm, is the type of protoplasm that makes up the cell nucleus, the most prominent organelle of the eukaryotic cell. It is enclosed by the nuclear envelope, also known as the nuclear membrane. The nucleoplasm resembles the cytoplasm of a eukaryotic cell in that it is a gel-like substance found within a membrane, although the nucleoplasm only fills out the space in the nucleus and has its own unique functions. The nucleoplasm suspends structures within the nucleus that are not membrane-bound and is responsible for maintaining the shape of the nucleus. The structures suspended in the nucleoplasm include chromosomes, various proteins, nuclear bodies, the nucleolus, nucleoporins, nucleotides, and nuclear speckles.

Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized. Telophase accounts for approximately 2% of the cell cycle's duration.

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

Lamins, also known as nuclear lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with inner nuclear membrane proteins to form the nuclear lamina on the interior of the nuclear envelope. Lamins have elastic and mechanosensitive properties, and can alter gene regulation in a feedback response to mechanical cues. Lamins are present in all animals but are not found in microorganisms, plants or fungi. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during mitosis, the positioning of nuclear pores, and programmed cell death. Mutations in lamin genes can result in several genetic laminopathies, which may be life-threatening.

Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate Branchiostoma.

The nuclear lamina is a dense fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division. Additionally, it participates in chromatin organization and it anchors the nuclear pore complexes embedded in the nuclear envelope.

Enaptin also known as nesprin-1 or synaptic nuclear envelope protein 1 (syne-1) is an actin-binding protein that in humans that is encoded by the SYNE1 gene.

<span class="mw-page-title-main">Protein filament</span> Long chain of protein monomers

In biology, a protein filament is a long chain of protein monomers, such as those found in hair, muscle, or in flagella. Protein filaments form together to make the cytoskeleton of the cell. They are often bundled together to provide support, strength, and rigidity to the cell. When the filaments are packed up together, they are able to form three different cellular parts. The three major classes of protein filaments that make up the cytoskeleton include: actin filaments, microtubules and intermediate filaments.

Emerin is a protein that in humans is encoded by the EMD gene, also known as the STA gene. Emerin, together with LEMD3, is a LEM domain-containing integral protein of the inner nuclear membrane in vertebrates. Emerin is highly expressed in cardiac and skeletal muscle. In cardiac muscle, emerin localizes to adherens junctions within intercalated discs where it appears to function in mechanotransduction of cellular strain and in beta-catenin signaling. Mutations in emerin cause X-linked recessive Emery–Dreifuss muscular dystrophy, cardiac conduction abnormalities and dilated cardiomyopathy.

KASH domains are conserved C-terminal protein regions less than ~30 amino acids. KASH is an acronym for Klarsicht, ANC-1, Syne Homology. KASH domains always follow a transmembrane domain. Most proteins containing KASH domains are thought to be involved in the positioning of the nucleus in the cell. KASH domains interact with proteins containing SUN domains in the space between the outer and inner nuclear membranes to bridge the nuclear envelope, and may transfer force from the nucleoskeleton to the cytoplasmic cytoskeleton and enable mechanosensory roles in cells. KASH proteins are thought to largely localize to the outer nuclear membrane, although there are reports of inner nuclear membrane localization of some KASH protein isoforms.

SUNdomains are conserved C-terminal protein regions a few hundred amino acids long. SUN domains are usually found following a transmembrane domain and a less conserved region of amino acids. Most proteins containing SUN domains are thought to be involved in the positioning of the nucleus in the cell. It is thought that SUN domains interact directly with KASH domains in the space between the outer and inner nuclear membranes to bridge the nuclear envelope and transfer force from the nucleoskeleton to the cytoplasmic cytoskeleton which enables mechanosensory roles in cells. SUN proteins are thought to localize to the inner nuclear membrane. The S. pombe Sad1 protein localises at the spindle pole body. In mammals, the SUN domain is present in two proteins, Sun1 and Sun2. The SUN domain of Sun2 has been demonstrated to be in the periplasm.

Lamina-associated polypeptide 2 (LAP2), isoforms beta/gamma is a protein that in humans is encoded by the TMPO gene. LAP2 is an inner nuclear membrane (INM) protein.

<span class="mw-page-title-main">LIM domain</span> InterPro Domain

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. 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.

The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material.

Nesprin-2 is a protein that in humans is encoded by the SYNE2 gene. The human SYNE2 gene consists of 116 exons and encodes nesprin-2, a member of the nuclear envelope (NE) spectrin-repeat (nesprin) family. Nesprins are modular proteins with a central extended spectrin-repeat (SR) rod domain and a C-terminal Klarsicht/ANC-1/Syne homology (KASH) transmembrane domain, which acts as a NE-targeting motif. Nesprin-2 (Nesp2) binds to cytoplasmic F-actin, tethering the nucleus to the cytoskeleton and maintaining the structural integrity of the nucleus.

Lamin-B1 is a protein that in humans is encoded by the LMNB1 gene.

Nesprins are a family of proteins that are found primarily in the outer nuclear membrane, as well as other subcellular compartments. They contain a C-terminal KASH transmembrane domain and are part of the LINC complex which is a protein network that associates the nuclear envelope to the cytoskeleton, outside the nucleus, and the nuclear lamina, inside the nucleus. Nesprin-1 and -2 bind to the actin filaments. Nesprin-3 binds to plectin, which is bound to the intermediate filaments, while nesprin-4 interacts with kinesin-1.

<span class="mw-page-title-main">Inner nuclear membrane protein</span> Protein embedded in inner membrane of nuclear envelope

Inner nuclear membrane proteins are membrane proteins that are embedded in or associated with the inner membrane of the nuclear envelope. There are about 60 INM proteins, most of which are poorly characterized with respect to structure and function. Among the few well-characterized INM proteins are lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1), lamina-associated polypeptide-2 (LAP2), emerin and MAN1.

References

1 2 King, Megan C. (2023). "Dynamic regulation of LINC complex composition and function across tissues and contexts". FEBS Letters. 597 (22): 2823–2832. doi:10.1002/1873-3468.14757. ISSN 1873-3468. PMID 37846646.
↑ Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D (January 2006). "Coupling of the nucleus and cytoplasm: role of the LINC complex". The Journal of Cell Biology. 172 (1): 41–53. doi:10.1083/jcb.200509124. PMC 2063530 . PMID 16380439.
1 2 van Ingen, Maria J. A.; Kirby, Tyler J. (2021-07-21). "LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function". Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.690577 . ISSN 2296-634X. PMC 8335485 . PMID 34368139.
1 2 Uzer, Gunes; Rubin, Clinton T.; Rubin, Janet (2016-03-01). "Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex". Current Molecular Biology Reports. 2 (1): 36–47. doi:10.1007/s40610-016-0032-8. ISSN 2198-6428. PMC 4912015 . PMID 27326387.
↑ Zi-yi, Zhou; Qin, Qin; Fei, Zhou; Cun-Yu, Cao; Lin, Teng (2024-04-02). "Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction". Cell Communication and Signaling. 22 (1): 208. doi: 10.1186/s12964-024-01593-y . ISSN 1478-811X. PMC 10986154 . PMID 38566066.
↑ van Ingen, Maria J. A.; Kirby, Tyler J. (2021-07-21). "LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function". Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.690577 . ISSN 2296-634X.
1 2 Driscoll, Tristan P.; Cosgrove, Brian D.; Heo, Su-Jin; Shurden, Zach E.; Mauck, Robert L. (June 2015). "Cytoskeletal to Nuclear Strain Transfer Regulates YAP Signaling in Mesenchymal Stem Cells". Biophysical Journal. 108 (12): 2783–2793. Bibcode:2015BpJ...108.2783D. doi:10.1016/j.bpj.2015.05.010. PMC 4472080 . PMID 26083918. S2CID 22081710.

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[:02-1] 1 2 King, Megan C. (2023). "Dynamic regulation of LINC complex composition and function across tissues and contexts". FEBS Letters. 597 (22): 2823–2832. doi:10.1002/1873-3468.14757. ISSN 1873-3468. PMID 37846646.

[2] Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D (January 2006). "Coupling of the nucleus and cytoplasm: role of the LINC complex". The Journal of Cell Biology. 172 (1): 41–53. doi:10.1083/jcb.200509124. PMC 2063530 . PMID 16380439.

[:0-3] 1 2 van Ingen, Maria J. A.; Kirby, Tyler J. (2021-07-21). "LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function". Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.690577 . ISSN 2296-634X. PMC 8335485 . PMID 34368139.

[:2-4] 1 2 Uzer, Gunes; Rubin, Clinton T.; Rubin, Janet (2016-03-01). "Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex". Current Molecular Biology Reports. 2 (1): 36–47. doi:10.1007/s40610-016-0032-8. ISSN 2198-6428. PMC 4912015 . PMID 27326387.

[5] Zi-yi, Zhou; Qin, Qin; Fei, Zhou; Cun-Yu, Cao; Lin, Teng (2024-04-02). "Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction". Cell Communication and Signaling. 22 (1): 208. doi: 10.1186/s12964-024-01593-y . ISSN 1478-811X. PMC 10986154 . PMID 38566066.

[6] van Ingen, Maria J. A.; Kirby, Tyler J. (2021-07-21). "LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function". Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.690577 . ISSN 2296-634X.

[:1-7] 1 2 Driscoll, Tristan P.; Cosgrove, Brian D.; Heo, Su-Jin; Shurden, Zach E.; Mauck, Robert L. (June 2015). "Cytoskeletal to Nuclear Strain Transfer Regulates YAP Signaling in Mesenchymal Stem Cells". Biophysical Journal. 108 (12): 2783–2793. Bibcode:2015BpJ...108.2783D. doi:10.1016/j.bpj.2015.05.010. PMC 4472080 . PMID 26083918. S2CID 22081710.

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