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.

MODULE:linc_complexDRAFTABSTRACTProtein Complexmodules/linc_complex.yaml
LINC complexGO:0106094
PMID:22632968
LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins.
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.
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.
PMID:16380439
Coupling of the nucleus and cytoplasm: role of the LINC complex.
Defines the LINC complex: SUN1 and SUN2 tether nesprin-2 Giant in the outer nuclear membrane through interactions spanning the perinuclear space.
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).

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.

16Nodes
3Parts
2Variant Sets
12Variants
14Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • linc_complex-deep-research-falcon.md (falcon)

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 4 evidence or coverage gap(s) (24 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
sun_kash_anchor SUN1
UniProtKB:O94901
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sun_kash_anchor SUN2
UniProtKB:Q9UH99
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sun_lamina_anchor SUN2
UniProtKB:Q9UH99
Family Representative 		lamin binding
GO:0005521 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sun_lamina_anchor SUN1
UniProtKB:O94901
Family Representative 		lamin binding
GO:0005521 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sun5_head_tail_anchor SUN5
UniProtKB:Q8TC36
Gene 		protein-membrane adaptor activity
GO:0043495 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fungal_sun_spb_anchor sad1 (S. pombe)
UniProtKB:Q09825
Family Representative 		spindle pole body-nuclear membrane anchor activity
GO:0106166 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fungal_sun_spb_anchor MPS3 (S. cerevisiae)
UniProtKB:P47069
Family Representative 		spindle pole body-nuclear membrane anchor activity
GO:0106166 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plant_sun_wip_anchor SUN1 (A. thaliana)
UniProtKB:Q9FF75
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
plant_sun_wip_anchor SUN2 (A. thaliana)
UniProtKB:Q9SG79
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nesprin_1_2_anchor SYNE2 (nesprin-2)
UniProtKB:Q8WXH0
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nesprin_1_2_anchor SYNE1 (nesprin-1)
UniProtKB:Q8NF91
Family Representative 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nesprin_3_plectin_anchor SYNE3 (nesprin-3)
UniProtKB:Q6ZMZ3
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nesprin_4_kinesin_anchor SYNE4 (nesprin-4)
UniProtKB:Q8N205
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
kash5_dynein_anchor KASH5
UniProtKB:Q8N6L0
Gene 		cytoskeletal motor activator activity
GO:0140660 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
unc83_kash_motor_adaptor unc-83 (C. elegans)
UniProtKB:Q23064
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
klar_mtoc_nucleus_anchor klar (D. melanogaster)
UniProtKB:Q9Y0E4
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
kms1_spb_telomere_anchor kms1 (S. pombe)
UniProtKB:P87245
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
wip1_sun_anchor WIP1 (A. thaliana)
UniProtKB:Q8GXA4
Gene 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
torsin_a_atpase TOR1A (torsinA)
UniProtKB:O14656
Gene 		ATP hydrolysis activity
GO:0016887 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sun_kash_anchor SUN-domain proteins (SUN1, SUN2)
PANTHER:PTHR12911
Family 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Family Supported
Family review supports GO:0140444 FAMILY_WIDE. Nearly every member review selects it as the core molecular function: human SUN1/SUN2, worm UNC-84 and SUN-1, Sad1, Mps3 (meiotic t-LINC), Arabidopsis SUN1/SUN2 and Koi. Each retains KASH partners that engage microtubule motors, the spindle pole body or actin. The SUN5 review uses the parent GO:0043495 because SUN5's partner structure is the sperm head-tail coupling apparatus. That is still a centriole-based cytoskeletal structure, so the child term is not contradicted. PAINT currently asserts only the parent GO:0043495 at the root PTN000308195. Asserting GO:0140444 there would match the member reviews.
sun_lamina_anchor SUN-domain proteins (SUN1, SUN2)
PANTHER:PTHR12911
Family 		lamin binding
GO:0005521 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0005521.
fungal_sun_spb_anchor fungal SUN proteins (Sad1, Mps3)
PANTHER:PTHR12911
Family 		spindle pole body-nuclear membrane anchor activity
GO:0106166 		Family Function Unreviewed
The family review has no applicable adjudication supporting or excluding GO:0106166.
plant_sun_wip_anchor plant C-terminal SUN proteins
PANTHER:PTHR12911
Family 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Family Supported
Family review supports GO:0140444 FAMILY_WIDE. Nearly every member review selects it as the core molecular function: human SUN1/SUN2, worm UNC-84 and SUN-1, Sad1, Mps3 (meiotic t-LINC), Arabidopsis SUN1/SUN2 and Koi. Each retains KASH partners that engage microtubule motors, the spindle pole body or actin. The SUN5 review uses the parent GO:0043495 because SUN5's partner structure is the sperm head-tail coupling apparatus. That is still a centriole-based cytoskeletal structure, so the child term is not contradicted. PAINT currently asserts only the parent GO:0043495 at the root PTN000308195. Asserting GO:0140444 there would match the member reviews.
nesprin_1_2_anchor giant nesprins (nesprin-1, nesprin-2)
PANTHER:PTHR14514
Family 		cytoskeleton-nuclear membrane anchor activity
GO:0140444 		Family Scope Restricted
GO:0140444 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. The defining function of the KASH-bearing nesprins (SF3, SF4), accepted as core in both human nesprin reviews and used for them in the linc_complex and nucleokinesis modules. It must not descend to vertebrate AKAP6 (SF2). AKAP6 lacks the KASH domain and is itself anchored to the nuclear envelope by nesprin-1alpha. The uncharacterized KASH-bearing sea-urchin (SF7) and amphioxus (SF2) proteins are plausible but untested carriers.

Gene-review completeness (16/17 grounded genes reviewed)

14 complete review(s) · 16 with deep research · 1 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
KASH5 Q8N6L0 ✓ ✓ ✓
klar Q9Y0E4 ✓ ✓ ✓
kms1 P87245 ✓ ✓ ✓
MPS3 P47069 ✓ ✓ ✓
TOR1A (torsinA) O14656 ✗ — —
sad1 Q09825 ✓ ✓ ✓
SUN1 O94901 ✓ ✓ ✓
SUN1 Q9FF75 ✓ ✓ ✓
SUN2 Q9SG79 ✓ ✓ ✓
SUN2 Q9UH99 ✓ ✓ ✓
SUN5 Q8TC36 ✓ ✓ ✓
SYNE1 Q8NF91 ✓ 56/57 ✓
SYNE2 Q8WXH0 ✓ 55/56 ✓
SYNE3 Q6ZMZ3 ✓ ✓ ✓
SYNE4 Q8N205 ✓ ✓ ✓
unc-83 Q23064 ✓ ✓ ✓
WIP1 Q8GXA4 ✓ ✓ ✓

Details

Context
EukaryotaNCBITaxon:2759
nuclear envelopeGO:0005635 nuclear envelope lumen (perinuclear space)GO:0005641
LINC complexProtein Complexlinc_complex

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.

LINC complexGO:0106094
Context
EukaryotaNCBITaxon:2759
nuclear envelopeGO:0005635 nuclear envelope lumen (perinuclear space)GO:0005641

Connections

SUN trimers bind KASH peptides in the perinuclear space and are required to keep KASH proteins in the outer nuclear membrane.
torsin_linc_regulation -> kash_component Positively Regulates
TorsinA with LAP1 promotes assembly of nesprin-2G/SUN2 TAN lines and the mobility of nesprin-2G within the nuclear envelope.
Part 1: inner-nuclear-membrane SUN component binding KASH peptides and the nucleoskeleton
SUN inner-nuclear-membrane componentProtein Complexsun_component

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.

PMID:22632968
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 set: SUN paralog by cell context by somatic vs germline SUN proteins (One Or More)
Somatic SUN1/SUN2Protein Complexsomatic_sun1_sun2

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

SUN1/SUN2 KASH-binding anchor
sun_kash_anchor
Participant: Family: SUN-domain proteins (SUN1, SUN2)
Family:
SUN-domain proteins (SUN1, SUN2)PANTHER:PTHR12911
Representative Members: SUN1UniProtKB:O94901 SUN2UniProtKB:Q9UH99

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: KASH peptides of nesprins and KASH5

Locations

nuclear inner membraneGO:0005637

Binds KASH peptides in the perinuclear space and holds KASH proteins in the outer nuclear membrane.

PMID:16380439
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.
PMID:19509342
SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice.
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.
SUN1/SUN2 nucleoplasmic lamina anchor
sun_lamina_anchor
Participant: Family: SUN-domain proteins (SUN1, SUN2)
Family:
SUN-domain proteins (SUN1, SUN2)PANTHER:PTHR12911
Representative Members: SUN2UniProtKB:Q9UH99 SUN1UniProtKB:O94901

Function

lamin bindingGO:0005521
Targets: A-type lamins

Processes

nuclear matrix anchoring at nuclear membraneGO:0090292

Locations

nuclear inner membraneGO:0005637

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.

Germline SUN5 at the sperm head-tail junctionProtein Complexgermline_sun5

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

SUN5 sperm head-tail anchor
sun5_head_tail_anchor
Participant: Gene Product: SUN5
Gene Product:
SUN5UniProtKB:Q8TC36

Function

protein-membrane adaptor activityGO:0043495 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: nesprin-3

Processes

spermatid developmentGO:0007286

Locations

nuclear inner membraneGO:0005637 sperm head-tail coupling apparatusGO:0120212
PMID:27640305
Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome.
SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm.
PMID:34268309
SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice.
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.
Fungal SUN proteins (Sad1, Mps3) anchoring the spindle pole bodyProtein Complexfungal_sun_spb

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

Fungal SUN spindle pole body anchor
fungal_sun_spb_anchor
Participant: Family: fungal SUN proteins (Sad1, Mps3)
Family:
fungal SUN proteins (Sad1, Mps3)PANTHER:PTHR12911
Representative Members: sad1 (S. pombe)UniProtKB:Q09825 MPS3 (S. cerevisiae)UniProtKB:P47069

Function

spindle pole body-nuclear membrane anchor activityGO:0106166

Processes

spindle pole body duplicationGO:0030474

Locations

nuclear inner membraneGO:0005637
PMID:16923827
provide evidence that it interacts with the Mps2 C terminus to tether the half-bridge to the core SPB
PMID:12486115
Execution point experiments revealed that MPS3 function is required for the first step of SPB duplication in G1.
PMID:30462301
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)
Plant C-terminal SUN proteins (AtSUN1, AtSUN2)Protein Complexplant_sun

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

AtSUN1/AtSUN2 WIP anchor
plant_sun_wip_anchor
Participant: Family: plant C-terminal SUN proteins
Family:
plant C-terminal SUN proteinsPANTHER:PTHR12911
Representative Members: SUN1 (A. thaliana)UniProtKB:Q9FF75 SUN2 (A. thaliana)UniProtKB:Q9SG79

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: WIP/SINE/TIK KASH-analog proteins

Locations

nuclear inner membraneGO:0005637
PMID:22270916
Here, we show that AtWIP1, AtWIP2, and AtWIP3 interact with AtSUN1 and AtSUN2 at the NE
Part 2: outer-nuclear-membrane KASH component coupling the bridge to a cytoskeletal system
KASH outer-nuclear-membrane componentProtein Complexkash_component

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 set: KASH protein by cytoskeletal partner by cytoskeletal system engaged (actin and microtubule motors; intermediate filaments; kinesin-1; meiotic dynein) (One Or More)

Several KASH proteins can be present in the same cell, so the variants are not mutually exclusive.

Nesprin-1/2 (actin and microtubule motors)Protein Complexnesprin_1_2_actin_motor

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

Nesprin-1/2 cytoskeletal anchor
nesprin_1_2_anchor
Participant: Family: giant nesprins (nesprin-1, nesprin-2)
Family:
giant nesprins (nesprin-1, nesprin-2)PANTHER:PTHR14514 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).
Representative Members: SYNE2 (nesprin-2)UniProtKB:Q8WXH0 SYNE1 (nesprin-1)UniProtKB:Q8NF91

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: actin filaments dynein-dynactin (through BICD2) kinesin-1

Processes

nuclear migration along microfilamentGO:0031022 nuclear migrationGO:0007097

Locations

nuclear outer membraneGO:0005640
PMID:16330710
Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin.
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).
PMID:20724637
Linear arrays of nuclear envelope proteins harness retrograde actin flow for nuclear movement.
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.
PMID:32619477
Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo.
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.
Nesprin-3 (plectin and intermediate filaments)Protein Complexnesprin_3_intermediate_filament

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

Nesprin-3 plectin anchor
nesprin_3_plectin_anchor
Participant: Gene Product: SYNE3 (nesprin-3)
Gene Product:
SYNE3 (nesprin-3)UniProtKB:Q6ZMZ3

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: plectin

Locations

nuclear outer membraneGO:0005640
PMID:16330710
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.
Nesprin-4 (kinesin-1)Protein Complexnesprin_4_kinesin

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

Nesprin-4 kinesin-1 anchor
nesprin_4_kinesin_anchor
Participant: Gene Product: SYNE4 (nesprin-4)
Gene Product:
SYNE4 (nesprin-4)UniProtKB:Q8N205

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: kinesin-1

Locations

nuclear outer membraneGO:0005640
PMID:19164528
Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization.
Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM.
PMID:23348741
The LINC complex is essential for hearing.
The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound.
PMID:36211453
A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells.
The LEWD kinesin-1-binding motif of nesprin-4 is required for nuclear positioning in outer hair cells.
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.
KASH5 with SUN1 (meiotic telomere attachment)Protein Complexkash5_meiotic

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.

meiotic LINC complexGO:0034993

Annotons

KASH5 meiotic dynein activating adaptor
kash5_dynein_anchor
Participant: Gene Product: KASH5
Gene Product:
KASH5UniProtKB:Q8N6L0

Function

cytoskeletal motor activator activityGO:0140660 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: dynein-dynactin (via DYNC1LI1/2) SUN1

Processes

meiotic telomere clusteringGO:0045141

Locations

nuclear outer membraneGO:0005640
PMID:22826121
A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis.
KASH5 possesses hitherto unknown KASH-related sequences that directly interacted with SUN1 and mediated telomere localization.
PMID:24062341
A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton.
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.
PMID:35703493
The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor.
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.
PMID:36946995
The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein.
KASH5 interacts with a dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved helix in the LIC C-terminal
PMID:17543860
SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice.
SUN1 is the inner-nuclear-membrane partner that binds meiotic telomeres.
Disruption of Sun1 in mice prevents telomere attachment to the nuclear envelope, efficient homolog pairing, and synapsis formation in meiosis.
C. elegans UNC-83 (kinesin-1 and dynein regulators)Protein Complexworm_unc83_motor_hub

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

UNC-83 KASH motor adaptor
unc83_kash_motor_adaptor
Participant: Gene Product: unc-83 (C. elegans)
Gene Product:
unc-83 (C. elegans)UniProtKB:Q23064

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: UNC-84 (SUN) kinesin-1 (KLC-2) NUD-2/LIS-1, BICD-1, DLC-1

Processes

nuclear migration along microtubuleGO:0030473

Locations

nuclear outer membraneGO:0005640
PMID:16481402
At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain
PMID:19605495
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
PMID:20005871
These data demonstrate that UNC-83 recruits NUD-2 to the nuclear envelope through a direct interaction in vivo.
Drosophila Klarsicht (with Klaroid/SUN)Protein Complexfly_klarsicht

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

Klarsicht MTOC-nucleus anchor
klar_mtoc_nucleus_anchor
Participant: Gene Product: klar (D. melanogaster)
Gene Product:
klar (D. melanogaster)UniProtKB:Q9Y0E4

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: Klaroid (SUN) microtubule organizing center

Processes

nuclear migrationGO:0007097

Locations

nuclear outer membraneGO:0005640
PMID:14617811
Here, we show that Klarsicht is required for connecting the microtubule organizing center (MTOC) to the nucleus.
PMID:18820457
we find that klaroid and klarsicht are required for nuclear migration in differentiating neurons and in non-neural cells
S. pombe Kms1 with Sad1 (meiotic telomere bouquet)Protein Complexfission_yeast_kms1

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.

Sad1-Kms1 LINC complexGO:1990612

Annotons

Kms1 meiotic SPB anchor
kms1_spb_telomere_anchor
Participant: Gene Product: kms1 (S. pombe)
Gene Product:
kms1 (S. pombe)UniProtKB:P87245

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: Sad1 (SUN)

Processes

meiotic telomere clusteringGO:0045141

Locations

nuclear outer membraneGO:0005640
PMID:27889481
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.
Plant WIP-WIT-myosin XI-i (actin coupling)Protein Complexplant_wip_actomyosin

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

WIP1 plant KASH-analog anchor
wip1_sun_anchor
Participant: Gene Product: WIP1 (A. thaliana)
Gene Product:
WIP1 (A. thaliana)UniProtKB:Q8GXA4

Function

cytoskeleton-nuclear membrane anchor activityGO:0140444
Targets: AtSUN1/AtSUN2 WIT1/WIT2 and myosin XI-i

Locations

nuclear outer membraneGO:0005640
PMID:22270916
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.
PMID:23973298
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.
Part 3: torsinA-dependent assembly of LINC complexes into force-bearing TAN lines (optional)
TorsinA regulation of LINC assemblyRegulatory Steptorsin_linc_regulation

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

TorsinA luminal AAA+ ATPase
torsin_a_atpase
Participant: Gene Product: TOR1A (torsinA)
Gene Product:
TOR1A (torsinA)UniProtKB:O14656

Function

ATP hydrolysis activityGO:0016887 ATPase activity depends on the LAP1 (or LULL1) activator.

Locations

nuclear envelope lumenGO:0005641
PMID:28242745
TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement.
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.