LINC complex (SUN-KASH nuclear envelope bridge) module

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.

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/<ORG>/, 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.