id: MODULE:linc_complex title: LINC complex (SUN-KASH nuclear envelope bridge) module description: >- The LINC (linker of nucleoskeleton and cytoskeleton) complex is a transmembrane bridge across the nuclear envelope. It connects the cytoskeleton to the nuclear interior. Inner-nuclear-membrane SUN-domain proteins form trimers whose C-terminal SUN domains project into the perinuclear space. Each trimer binds the C-terminal KASH peptides of three outer-nuclear-membrane KASH proteins, and the pair is reinforced by a conserved intermolecular disulfide. On the nucleoplasmic side, SUN proteins bind the nuclear lamina and, in meiosis, telomeres. On the cytoplasmic side, different KASH proteins engage different cytoskeletal systems: nesprin-1 and nesprin-2 bind actin through calponin-homology domains and bind microtubule motors (dynein-dynactin through BICD2, and kinesin-1); nesprin-3 binds plectin and so intermediate filaments; nesprin-4 binds kinesin-1; and the meiosis-specific KASH5 recruits dynein-dynactin. The bridge transmits force for nuclear migration and anchorage, centrosome-nucleus coupling, meiotic telomere-led chromosome movement, and sperm head-tail attachment. Disruption causes muscular dystrophy, cerebellar ataxia, hearing loss, infertility and neuronal migration defects. status: DRAFT scope: ABSTRACT evidence: - source_id: PMID:22632968 title: "LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins." statement: >- Crystal structures of human SUN2 with KASH1/KASH2 peptides define the core of the LINC complex: a SUN trimer binding three KASH peptides, with a covalent SUN-KASH disulfide. supporting_text: >- LINC formation relies on direct binding of KASH and SUN in the perinuclear space. Thereby, molecular tethers are formed that can transmit forces for chromosome movements, nuclear migration, and anchorage. - source_id: PMID:16380439 title: "Coupling of the nucleus and cytoplasm: role of the LINC complex." statement: >- Defines the LINC complex: SUN1 and SUN2 tether nesprin-2 Giant in the outer nuclear membrane through interactions spanning the perinuclear space. supporting_text: >- support a model in which Sun proteins tether nesprins in the ONM via interactions spanning the PNS. In this way, Sun proteins and nesprins form a complex that links the nucleoskeleton and cytoskeleton (the LINC complex). notes: >- Boundary. The module is the SUN-KASH bridge itself: the SUN inner-nuclear-membrane component, the KASH outer-nuclear-membrane component with its alternative cytoskeletal couplings, and torsinA as a directly acting regulator of LINC assembly into TAN lines. The cytoskeletal motors and filaments the KASH proteins engage (dynein, kinesin-1, actin, plectin/intermediate filaments), the nuclear lamina, and the processes that use the bridge (nucleokinesis, myonuclear anchorage, meiotic chromosome movement) are modelled as interfaces, not as parts. Nucleokinesis is modelled in MODULE:nucleokinesis, whose LINC variant conforms to this module. Complex term. GO:0106094 nuclear membrane microtubule tethering complex is used for the somatic complex. GO:0034993 meiotic nuclear membrane microtubule tethering complex is used only for the SUN1-KASH5 meiotic variant. GOA annotates much somatic evidence for SUN1, SUN2, SYNE1 and SYNE2 to GO:0034993; the gene reviews in this repository move those rows to GO:0106094. There is no GO molecular-function term for binding a KASH domain. The reviews use GO:0140444 cytoskeleton-nuclear membrane anchor activity for both SUN and KASH partners, and this module follows them. Domain grounding. SUN proteins share the SUN domain (InterPro IPR012919) and PANTHER family PTHR12911. The KASH proteins do not form a single PANTHER family: nesprin-1/2 are in PTHR14514, nesprin-3 in PTHR47535, nesprin-4 in PTHR21640 and KASH5 in PTHR47300. They share only the C-terminal KASH domain (InterPro IPR012315). KASH5 has a divergent KASH-like tail that is not matched by IPR012315. The KASH component is therefore modelled as variants, one per KASH protein, not as a family. Module deep research (modules/linc_complex-deep-research-falcon.md) agreed with this boundary. It added several qualifications, recorded in the relevant descriptions: - The 3:3 SUN-KASH unit is secure. Back-to-back 6:6 assemblies are seen with purified proteins, but their existence in cells is unresolved. - The SUN-KASH disulfide strengthens force transfer but is not universally required, and may be remodelled. - TorsinA is an accessory, context-specific regulator. - The meiotic telomere attachment plate and the sperm head-tail coupling apparatus contain many proteins that are not LINC subunits. The SUN component is deeply conserved across eukaryotes. KASH homology outside animals is uncertain; plant WIP/SINE proteins are functional analogs. Gene reviews. All LINC members have complete reviews (SUN1, SUN2, SUN5, SYNE1-4, KASH5). The reviews consistently move somatic GO:0034993 rows to GO:0106094 and protein-binding rows with SUN/KASH partners to GO:0140444. SUN5 also moved to GO:0106094, because its complex is post-meiotic. KASH5 and BICD2 both carry cytoskeletal motor activator activity (GO:0140660) in their reviews. TOR1A has no review yet. Comparative and family reviews. Model-organism orthologs are reviewed under genes//, and PANTHER family reviews are in interpro/panther/{PTHR12911,PTHR14514}/. - The SUN side is homologous across eukaryotes. Worm UNC-84 (somatic) and SUN-1 (meiotic) split the roles of human SUN1. - The KASH side is convergent. UNC-83, ANC-1, Klarsicht, Kms1, Mps2/Csm4 and the plant WIPs are functional analogs from different families. - The meiotic complex term is used beyond SUN1-KASH5: fly Klaroid/Klarsicht (centromere-based pairing), worm SUN-1/ZYG-12 and fission yeast Sad1-Kms1 (GO:1990612) also carry it. - The PAINT meiotic-complex node PTN000308197 over-reaches to somatic UNC-84 and the post-meiotic testis SUN clade. - GO:0106094 and GO:0034993 are defined as microtubule tethering, which misdescribes actin-coupled bridges: nesprin TAN lines, plant WIP-WIT, and budding yeast meiotic telomere movement through Myo2. The plant reviews use GO:0106083 instead, and a cytoskeleton-neutral LINC complex term would help. - Worm ANC-1 anchors nuclei largely independently of its CH domains and KASH-SUN link, through spectrin repeats and an ER anchor. The actin CH domains are therefore not universally essential for nesprin-type anchorage. Not yet modelled. SUN3 (Q8TAQ9) and SPAG4/SUN4 (Q9NPE6) act in spermatid nuclear shaping and have no gene reviews here. The same is true of KASH6 and other lineage-specific KASH proteins, and of emerin/lamin interfaces beyond SUN-lamin binding. Worm ANC-1 (ER-anchored giant KASH), fly Msp300 and budding yeast Mps2/Csm4 are described in their gene reviews but not modelled as variants. module: id: linc_complex label: LINC complex module_type: PROTEIN_COMPLEX description: >- Nuclear envelope bridge formed by inner-nuclear-membrane SUN trimers bound in the perinuclear space to outer-nuclear-membrane KASH proteins, which in turn engage actin, microtubule motors or intermediate filaments. concepts: - preferred_term: LINC complex term: id: GO:0106094 label: nuclear membrane microtubule tethering complex description: >- Somatic SUN-KASH complex linking the nuclear lumen to the cytoskeleton. context: taxa: - preferred_term: Eukaryota term: id: NCBITaxon:2759 label: Eukaryota description: >- SUN-KASH bridges occur in animals, fungi, amoebozoans and plants; the KASH proteins and their cytoplasmic partners diverge widely. Exemplars here are human. cellular_components: - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope - preferred_term: nuclear envelope lumen (perinuclear space) term: id: GO:0005641 label: nuclear envelope lumen parts: - order: 1 role: inner-nuclear-membrane SUN component binding KASH peptides and the nucleoskeleton node: id: sun_component label: SUN inner-nuclear-membrane component module_type: PROTEIN_COMPLEX description: >- SUN-domain proteins span the inner nuclear membrane as trimers. Their luminal SUN domains each bind KASH peptides at the interfaces between adjacent SUN domains. Their nucleoplasmic N-termini bind the lamina and, in meiosis, telomeres. evidence: - source_id: PMID:22632968 supporting_text: >- The SUN2 domain is rigidly attached to a trimeric coiled coil that prepositions it to bind three KASH peptides. The peptides bind in three deep and expansive grooves formed between adjacent SUN domains, effectively acting as molecular glue. variant_sets: - id: sun_paralog_context label: SUN paralog by cell context axis: somatic vs germline SUN proteins selection: ONE_OR_MORE variants: - id: somatic_sun1_sun2 label: Somatic SUN1/SUN2 module_type: PROTEIN_COMPLEX description: >- SUN1 and SUN2 are broadly expressed and largely redundant. Together they are required to hold nesprins in the outer nuclear membrane, for example in skeletal muscle, where they anchor myonuclei through nesprin-1. SUN1 alone forms the meiotic telomere-attachment complex with KASH5. annotons: - id: sun_kash_anchor label: SUN1/SUN2 KASH-binding anchor participant: selector_type: FAMILY family: preferred_term: SUN-domain proteins (SUN1, SUN2) term: id: PANTHER:PTHR12911 label: SAD1/UNC-84-LIKE PROTEIN-RELATED representative_members: - preferred_term: SUN1 term: id: UniProtKB:O94901 label: SUN domain-containing protein 1 - preferred_term: SUN2 term: id: UniProtKB:Q9UH99 label: SUN domain-containing protein 2 ancestral_nodes: - preferred_term: PAINT node PTN000308195 (Eukaryota root of PTHR12911) term: id: PANTHER:PTN000308195 label: PTN000308195 description: >- Root PAINT IBD node of the SUN family, asserting nuclear envelope (GO:0005635) and protein-membrane adaptor activity (GO:0043495). The PTHR12911 family review scopes SUN-KASH anchoring (GO:0140444) as family-wide and proposes asserting it at this node. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000308195 in PTHR12911. - source_id: file:interpro/panther/PTHR12911/PTHR12911-review.yaml statement: Family review assessing the SUN-family PAINT nodes. function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: KASH peptides of nesprins and KASH5 locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane role_description: >- Binds KASH peptides in the perinuclear space and holds KASH proteins in the outer nuclear membrane. evidence: - source_id: PMID:16380439 supporting_text: >- Codepletion of both of these proteins in HeLa cells leads to the loss of ONM-associated nesp2G, as does overexpression of the Sun1 lumenal domain. - source_id: PMID:19509342 title: "SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice." supporting_text: >- These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning. - id: sun_lamina_anchor label: SUN1/SUN2 nucleoplasmic lamina anchor participant: selector_type: FAMILY family: preferred_term: SUN-domain proteins (SUN1, SUN2) term: id: PANTHER:PTHR12911 label: SAD1/UNC-84-LIKE PROTEIN-RELATED representative_members: - preferred_term: SUN2 term: id: UniProtKB:Q9UH99 label: SUN domain-containing protein 2 - preferred_term: SUN1 term: id: UniProtKB:O94901 label: SUN domain-containing protein 1 function: preferred_term: lamin binding term: id: GO:0005521 label: lamin binding targets: - preferred_term: A-type lamins processes: - preferred_term: nuclear matrix anchoring at nuclear membrane term: id: GO:0090292 label: nuclear matrix anchoring at nuclear membrane locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane role_description: >- Couples the bridge to the nuclear lamina, so that cytoplasmic force is transmitted to the nuclear interior. Lamin binding is a core function in both the SUN1 and SUN2 reviews. - id: germline_sun5 label: Germline SUN5 at the sperm head-tail junction module_type: PROTEIN_COMPLEX description: >- The testis-specific SUN5 sits at the posterior nuclear envelope of elongating spermatids, where the head-tail coupling apparatus attaches. There it pairs with nesprin-3 to form a post-meiotic LINC complex that holds the sperm head to the tail. Loss of SUN5 causes acephalic (headless) spermatozoa; Sun5-knockout mice have normal meiosis. The requirement for SUN5 is firmer than the exact composition of the SUN5-nesprin-3 bridge. annotons: - id: sun5_head_tail_anchor label: SUN5 sperm head-tail anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SUN5 term: id: UniProtKB:Q8TC36 label: SUN domain-containing protein 5 function: preferred_term: protein-membrane adaptor activity term: id: GO:0043495 label: protein-membrane adaptor activity description: >- Core function in the SUN5 review. SUN5 anchors the head-tail coupling apparatus to the nuclear envelope; how a luminal SUN domain reaches its cytoplasmic partners (for example septin-12 and ODF1) is unresolved. targets: - preferred_term: nesprin-3 processes: - preferred_term: spermatid development term: id: GO:0007286 label: spermatid development locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane - preferred_term: sperm head-tail coupling apparatus term: id: GO:0120212 label: sperm head-tail coupling apparatus evidence: - source_id: PMID:27640305 title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome." supporting_text: >- SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm. - source_id: PMID:34268309 title: "SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice." supporting_text: >- Further coimmunoprecipitation (Co-IP) and immunofluorescence assays confirmed that Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex participating in the connection of the head and tail of spermatozoa. - id: fungal_sun_spb label: Fungal SUN proteins (Sad1, Mps3) anchoring the spindle pole body module_type: PROTEIN_COMPLEX description: >- Yeasts have a single main SUN protein that pairs with different KASH-like partners depending on context. S. pombe Sad1 anchors the spindle pole body (SPB), tethers centromeres and, with the KASH protein Kms1, clusters telomeres at the SPB in meiosis (GO:1990612). S. cerevisiae Mps3 anchors the SPB half-bridge through Mps2 and is required for SPB duplication; in meiosis it pairs with Csm4. This is the fungal counterpart of centrosome-nucleus coupling. annotons: - id: fungal_sun_spb_anchor label: Fungal SUN spindle pole body anchor participant: selector_type: FAMILY family: preferred_term: fungal SUN proteins (Sad1, Mps3) term: id: PANTHER:PTHR12911 label: SAD1/UNC-84-LIKE PROTEIN-RELATED representative_members: - preferred_term: sad1 (S. pombe) term: id: UniProtKB:Q09825 label: Spindle pole body-associated protein sad1 - preferred_term: MPS3 (S. cerevisiae) term: id: UniProtKB:P47069 label: Spindle pole body assembly component MPS3 function: preferred_term: spindle pole body-nuclear membrane anchor activity term: id: GO:0106166 label: spindle pole body-nuclear membrane anchor activity processes: - preferred_term: spindle pole body duplication term: id: GO:0030474 label: spindle pole body duplication locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane evidence: - source_id: PMID:16923827 supporting_text: >- provide evidence that it interacts with the Mps2 C terminus to tether the half-bridge to the core SPB - source_id: PMID:12486115 supporting_text: >- Execution point experiments revealed that MPS3 function is required for the first step of SPB duplication in G1. - source_id: PMID:30462301 supporting_text: >- Sad1 is a SUN-domain-containing inner-nuclear-membrane protein, and interacts with a KASH-domain-containing outer-nuclear-membrane Kms1 to form a trans-nuclear-membrane complex which is referred to as a linker of nucleoskeleton and cytoskeleton complex (LINC) - id: plant_sun label: Plant C-terminal SUN proteins (AtSUN1, AtSUN2) module_type: PROTEIN_COMPLEX description: >- Arabidopsis SUN1 and SUN2 anchor plant-specific KASH analogs (WIP, SINE and TIK proteins) through a conserved SUN domain. They control nuclear shape and meiotic telomere attachment. The plant bridge couples to actin (see the plant WIP variant), so the microtubule-defined GO:0106094 does not fit; the Arabidopsis reviews use GO:0106083 nuclear membrane protein complex. annotons: - id: plant_sun_wip_anchor label: AtSUN1/AtSUN2 WIP anchor participant: selector_type: FAMILY family: preferred_term: plant C-terminal SUN proteins term: id: PANTHER:PTHR12911 label: SAD1/UNC-84-LIKE PROTEIN-RELATED representative_members: - preferred_term: SUN1 (A. thaliana) term: id: UniProtKB:Q9FF75 label: SUN domain-containing protein 1 - preferred_term: SUN2 (A. thaliana) term: id: UniProtKB:Q9SG79 label: SUN domain-containing protein 2 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: WIP/SINE/TIK KASH-analog proteins locations: - preferred_term: nuclear inner membrane term: id: GO:0005637 label: nuclear inner membrane evidence: - source_id: PMID:22270916 supporting_text: >- Here, we show that AtWIP1, AtWIP2, and AtWIP3 interact with AtSUN1 and AtSUN2 at the NE - order: 2 role: outer-nuclear-membrane KASH component coupling the bridge to a cytoskeletal system node: id: kash_component label: KASH outer-nuclear-membrane component module_type: PROTEIN_COMPLEX description: >- KASH proteins are tail-anchored in the outer nuclear membrane. Their C-terminal KASH peptides enter the perinuclear space to bind SUN, and their cytoplasmic domains determine which cytoskeletal system the nucleus is coupled to. They are held in the outer nuclear membrane only when SUN proteins are present. variant_sets: - id: kash_cytoskeletal_coupling label: KASH protein by cytoskeletal partner axis: cytoskeletal system engaged (actin and microtubule motors; intermediate filaments; kinesin-1; meiotic dynein) selection: ONE_OR_MORE notes: >- Several KASH proteins can be present in the same cell, so the variants are not mutually exclusive. variants: - id: nesprin_1_2_actin_motor label: Nesprin-1/2 (actin and microtubule motors) module_type: PROTEIN_COMPLEX description: >- The giant nesprin-1 and nesprin-2 isoforms bind actin through N-terminal calponin-homology domains. Their spectrin-repeat rods bind dynein-dynactin through BICD2 and kinesin-1 through an LEWD motif. In polarizing fibroblasts, nesprin-2G and SUN2 assemble into transmembrane actin-associated nuclear (TAN) lines on dorsal actin cables that move the nucleus rearward. In muscle, nesprin-1 anchors and spaces myonuclei. annotons: - id: nesprin_1_2_anchor label: Nesprin-1/2 cytoskeletal anchor participant: selector_type: FAMILY family: preferred_term: giant nesprins (nesprin-1, nesprin-2) term: id: PANTHER:PTHR14514 label: PKA ANCHORING PROTEIN representative_members: - preferred_term: SYNE2 (nesprin-2) term: id: UniProtKB:Q8WXH0 label: Nesprin-2 - preferred_term: SYNE1 (nesprin-1) term: id: UniProtKB:Q8NF91 label: Nesprin-1 description: >- PTHR14514 also contains KASH-less AKAP6 (mAKAP), split off by a chordate duplication; nesprin-1/2 are subfamilies SF3/SF4. Invertebrate nesprin orthologs (ANC-1, Klarsicht, Msp300) fall in other PANTHER families (PTHR21524, PTHR47535). ancestral_nodes: - preferred_term: PAINT node PTN008556068 (Deuterostomia root of PTHR14514) term: id: PANTHER:PTN008556068 label: PTN008556068 description: >- Asserts cytoskeleton-nuclear membrane anchor activity (GO:0140444) and nuclear membrane. The PTHR14514 family review rates the GO:0140444 IBD as needing pruning: it should not reach the KASH-less AKAP6 clade (exclusion proposed at PTN002684320). evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008556068 in PTHR14514. - source_id: file:interpro/panther/PTHR14514/PTHR14514-review.yaml statement: Family review assessing the nesprin/AKAP6 PAINT nodes. - preferred_term: PAINT node PTN009019575 (nesprin-1/2 clade) term: id: PANTHER:PTN009019575 label: PTN009019575 description: >- Asserts nuclear migration (GO:0007097) and centrosome localization (GO:0051642); both hold in the family review. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN009019575 in PTHR14514. function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: actin filaments - preferred_term: dynein-dynactin (through BICD2) - preferred_term: kinesin-1 processes: - preferred_term: nuclear migration along microfilament term: id: GO:0031022 label: nuclear migration along microfilament - preferred_term: nuclear migration term: id: GO:0007097 label: nuclear migration locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:16330710 title: "Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin." supporting_text: >- Two related ONM proteins, nuclear envelope spectrin repeat (nesprin)-1 and -2, are known to make direct connections with the actin cytoskeleton through their NH2-terminal actin-binding domain (ABD). - source_id: PMID:20724637 title: "Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement." supporting_text: >- We found that linear arrays of outer (nesprin2G) and inner (SUN2) nuclear membrane proteins assembled on and moved with retrogradely moving dorsal actin cables during nuclear movement in polarizing fibroblasts. - source_id: PMID:32619477 title: "Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo." supporting_text: >- We find further that, surprisingly, the motor proteins interact with Nesprin-2 through the dynein/kinesin "adaptor" BicD2, both in neurons and in non-mitotic fibroblasts. - id: nesprin_3_intermediate_filament label: Nesprin-3 (plectin and intermediate filaments) module_type: PROTEIN_COMPLEX description: >- Nesprin-3 lacks an actin-binding domain. It binds the plakin plectin, which links the nucleus to the intermediate-filament cytoskeleton (keratins, vimentin or desmin, depending on cell type) and, through integrin alpha6beta4, to the extracellular matrix. It is broadly expressed and pairs with SUN1/SUN2; in spermatids it pairs with SUN5 (see the germline SUN5 variant). Nesprin-3 knockout mice have no gross phenotype. annotons: - id: nesprin_3_plectin_anchor label: Nesprin-3 plectin anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SYNE3 (nesprin-3) term: id: UniProtKB:Q6ZMZ3 label: Nesprin-3 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: plectin locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:16330710 supporting_text: >- We have now isolated a third member of the nesprin family that lacks an ABD and instead binds to the plakin family member plectin, which can associate with the intermediate filament (IF) system. - id: nesprin_4_kinesin label: Nesprin-4 (kinesin-1) module_type: PROTEIN_COMPLEX description: >- Nesprin-4 is expressed in secretory epithelia and in cochlear outer hair cells. It binds kinesin-1 through an LEWD motif (gene review: kinesin binding, GO:0019894) and can reposition the centrosome and Golgi relative to the nucleus. With SUN1, it keeps outer hair cell nuclei at the base of the cell, and its loss causes progressive hearing loss. annotons: - id: nesprin_4_kinesin_anchor label: Nesprin-4 kinesin-1 anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SYNE4 (nesprin-4) term: id: UniProtKB:Q8N205 label: Nesprin-4 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: kinesin-1 locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:19164528 title: "Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization." supporting_text: >- Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. - source_id: PMID:23348741 title: "The LINC complex is essential for hearing." supporting_text: >- The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound. - source_id: PMID:36211453 title: "A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells." statement: >- The LEWD kinesin-1-binding motif of nesprin-4 is required for nuclear positioning in outer hair cells. supporting_text: >- To test the hypothesis that the nucleus in OHC is positioned via kinesin-1 dependent cargo trafficking, we mutated the LEWD kinesin-binding domain in Nesprin-4. - id: kash5_meiotic label: KASH5 with SUN1 (meiotic telomere attachment) module_type: PROTEIN_COMPLEX description: >- In meiotic prophase I, SUN1 binds telomeres at the inner nuclear membrane and pairs with the germ-cell-specific KASH5 (SUN2 can partly substitute). KASH5 is a transmembrane dynein activating adaptor: its N-terminal EF-hands bind the dynein light intermediate chain, and with LIS1 and dynactin it turns dynein into a processive motor. Telomeres are thereby moved along cytoplasmic microtubules to cluster in the bouquet so that homologous chromosomes can pair. On the nucleoplasmic side, SUN1 is recruited to telomeres by the TRF1-TERB1-TERB2-MAJIN attachment plate, an interface rather than part of the complex. Loss of either SUN1 or KASH5 causes meiotic arrest and infertility. The KASH5 tail is divergent from canonical KASH domains but binds SUN in the same way. concepts: - preferred_term: meiotic LINC complex term: id: GO:0034993 label: meiotic nuclear membrane microtubule tethering complex annotons: - id: kash5_dynein_anchor label: KASH5 meiotic dynein activating adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: KASH5 term: id: UniProtKB:Q8N6L0 label: Protein KASH5 function: preferred_term: cytoskeletal motor activator activity term: id: GO:0140660 label: cytoskeletal motor activator activity description: >- Activates dynein-dynactin processivity (core function in the KASH5 review). KASH5 also binds SUN1 through its KASH-like tail (GO:0140444 in the review). Telomere attachment itself depends on SUN1, not KASH5. targets: - preferred_term: dynein-dynactin (via DYNC1LI1/2) - preferred_term: SUN1 processes: - preferred_term: meiotic telomere clustering term: id: GO:0045141 label: meiotic telomere clustering locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:22826121 title: "A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis." supporting_text: >- KASH5 possesses hitherto unknown KASH-related sequences that directly interacted with SUN1 and mediated telomere localization. - source_id: PMID:24062341 title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton." supporting_text: >- These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression. - source_id: PMID:35703493 title: "The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor." supporting_text: >- We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor. - source_id: PMID:36946995 title: "The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein." supporting_text: >- KASH5 interacts with a dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved helix in the LIC C-terminal - source_id: PMID:17543860 title: "SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice." statement: >- SUN1 is the inner-nuclear-membrane partner that binds meiotic telomeres. supporting_text: >- Disruption of Sun1 in mice prevents telomere attachment to the nuclear envelope, efficient homolog pairing, and synapsis formation in meiosis. - id: worm_unc83_motor_hub label: C. elegans UNC-83 (kinesin-1 and dynein regulators) module_type: PROTEIN_COMPLEX description: >- UNC-83 is a short KASH protein bound by the SUN protein UNC-84. It recruits kinesin-1 (through KLC-2) and the dynein regulators NUD-2/LIS-1, BICD-1 and DLC-1 to the nucleus, which then moves in hyp7 precursors and P cells. It lacks the SUN-KASH disulfide cysteine and has no InterPro KASH match. It is the worm counterpart of the nesprin-2/BICD2 motor hub. annotons: - id: unc83_kash_motor_adaptor label: UNC-83 KASH motor adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: unc-83 (C. elegans) term: id: UniProtKB:Q23064 label: Nuclear migration protein unc-83 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: UNC-84 (SUN) - preferred_term: kinesin-1 (KLC-2) - preferred_term: NUD-2/LIS-1, BICD-1, DLC-1 processes: - preferred_term: nuclear migration along microtubule term: id: GO:0030473 label: nuclear migration along microtubule locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:16481402 supporting_text: >- At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain - source_id: PMID:19605495 supporting_text: >- we show that UNC-83 also interacts with the kinesin-1 light chain KLC-2, as identified in a yeast two-hybrid screen and confirmed by in vitro assays - source_id: PMID:20005871 supporting_text: >- These data demonstrate that UNC-83 recruits NUD-2 to the nuclear envelope through a direct interaction in vivo. - id: fly_klarsicht label: Drosophila Klarsicht (with Klaroid/SUN) module_type: PROTEIN_COMPLEX description: >- The KASH isoform of Klarsicht, anchored by the SUN protein Klaroid, connects the MTOC to the nucleus for photoreceptor nuclear migration and spaces myonuclei. A separate isoform with a different C-terminus transports lipid droplets and is not part of the LINC complex. Klarsicht is in PANTHER PTHR21524, not the vertebrate nesprin family. annotons: - id: klar_mtoc_nucleus_anchor label: Klarsicht MTOC-nucleus anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: klar (D. melanogaster) term: id: UniProtKB:Q9Y0E4 label: Klarsicht protein function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: Klaroid (SUN) - preferred_term: microtubule organizing center processes: - preferred_term: nuclear migration term: id: GO:0007097 label: nuclear migration locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:14617811 supporting_text: >- Here, we show that Klarsicht is required for connecting the microtubule organizing center (MTOC) to the nucleus. - source_id: PMID:18820457 supporting_text: >- we find that klaroid and klarsicht are required for nuclear migration in differentiating neurons and in non-neural cells - id: fission_yeast_kms1 label: S. pombe Kms1 with Sad1 (meiotic telomere bouquet) module_type: PROTEIN_COMPLEX description: >- Kms1 is a KASH-like outer-nuclear-membrane protein without a canonical KASH motif. With Sad1 it forms the Sad1-Kms1 LINC complex that links the meiotic telomere bouquet to the SPB, and it couples DNA double-strand breaks to microtubules. Kms2 is Sad1's mitotic SPB partner. concepts: - preferred_term: Sad1-Kms1 LINC complex term: id: GO:1990612 label: Sad1-Kms1 LINC complex annotons: - id: kms1_spb_telomere_anchor label: Kms1 meiotic SPB anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: kms1 (S. pombe) term: id: UniProtKB:P87245 label: Karyogamy meiotic segregation protein 1 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: Sad1 (SUN) processes: - preferred_term: meiotic telomere clustering term: id: GO:0045141 label: meiotic telomere clustering locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:27889481 supporting_text: >- The linkage between the telomere bouquet and the SPB (on the outer surface of the NE during meiotic prophase) occurs via the LINC complex, which comprises the KASH-domain outer NE protein Kms1 and the SUN-domain inner NE protein Sad1. - id: plant_wip_actomyosin label: Plant WIP-WIT-myosin XI-i (actin coupling) module_type: PROTEIN_COMPLEX description: >- Plant WIP proteins are KASH analogs without sequence homology to nesprins (own PANTHER family). Their tails bind AtSUN1 and AtSUN2, and they recruit WIT1/WIT2, which anchor myosin XI-i to couple the nucleus to actin for nuclear movement and shape. WIPs also anchor RanGAP1 at the nuclear envelope. annotons: - id: wip1_sun_anchor label: WIP1 plant KASH-analog anchor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: WIP1 (A. thaliana) term: id: UniProtKB:Q8GXA4 label: WPP domain-interacting protein 1 function: preferred_term: cytoskeleton-nuclear membrane anchor activity term: id: GO:0140444 label: cytoskeleton-nuclear membrane anchor activity targets: - preferred_term: AtSUN1/AtSUN2 - preferred_term: WIT1/WIT2 and myosin XI-i locations: - preferred_term: nuclear outer membrane term: id: GO:0005640 label: nuclear outer membrane evidence: - source_id: PMID:22270916 supporting_text: >- we report that AtWIPs are plant-specific KASH proteins interacting with Arabidopsis SUN proteins (AtSUNs). The interaction is required for both AtWIP1 and AtRanGAP1 NE localization. - source_id: PMID:23973298 supporting_text: >- Myosin XI-i is specifically localized on the nuclear membrane, where it physically interacts with the outer-nuclear-membrane proteins WIT1 and WIT2. Both WIT proteins are required for anchoring myosin XI-i to the nuclear membrane and for nuclear movement. - order: 3 role: torsinA-dependent assembly of LINC complexes into force-bearing TAN lines optional: true node: id: torsin_linc_regulation label: TorsinA regulation of LINC assembly module_type: REGULATORY_STEP description: >- The AAA+ ATPase torsinA, which resides in the nuclear envelope lumen and is activated by the inner-nuclear-membrane protein LAP1, is required to assemble nesprin-2G/SUN2 TAN lines and for actin-dependent rearward nuclear movement in migrating fibroblasts. It is a context-specific regulator, not a general LINC assembly factor: its direct substrates are unknown, and whether it acts directly on SUN-KASH pairs is not settled. annotons: - id: torsin_a_atpase label: TorsinA luminal AAA+ ATPase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TOR1A (torsinA) term: id: UniProtKB:O14656 label: Torsin-1A function: preferred_term: ATP hydrolysis activity term: id: GO:0016887 label: ATP hydrolysis activity description: >- ATPase activity depends on the LAP1 (or LULL1) activator. locations: - preferred_term: nuclear envelope lumen term: id: GO:0005641 label: nuclear envelope lumen evidence: - source_id: PMID:28242745 title: "TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement." supporting_text: >- Both TA and LAP1 contributed to the assembly of transmembrane actin-associated nuclear (TAN) lines, which couple the nucleus to dorsal perinuclear actin cables undergoing retrograde flow. connections: - source: sun_component target: kash_component description: >- SUN trimers bind KASH peptides in the perinuclear space and are required to keep KASH proteins in the outer nuclear membrane. - source: torsin_linc_regulation target: kash_component connection_type: POSITIVELY_REGULATES description: >- TorsinA with LAP1 promotes assembly of nesprin-2G/SUN2 TAN lines and the mobility of nesprin-2G within the nuclear envelope.