SYNE2 encodes nesprin-2, a family of spectrin-repeat proteins produced from a very large gene by alternative promoters and splicing. The giant isoform (nesprin-2G, NUANCE, ~800 kDa) has N-terminal paired calponin-homology domains that bind F-actin, a long spectrin-repeat rod, and a C-terminal transmembrane KASH domain that anchors it in the outer nuclear membrane. In the perinuclear space the KASH peptide binds trimeric SUN1/SUN2 of the inner nuclear membrane, forming the LINC (linker of nucleoskeleton and cytoskeleton) complex that transmits cytoskeletal forces to the nuclear lamina. Nesprin-2G assembles with SUN2 into transmembrane actin-associated nuclear (TAN) lines that couple the nucleus to retrograde actin flow, moving the nucleus and reorienting the centrosome in migrating fibroblasts; the formin FHOD1 reinforces this coupling. Its membrane-proximal spectrin repeats also recruit microtubule motors to the nuclear envelope, kinesin-1 through a LEWD motif and dynein-dynactin through the adaptor BICD2, providing the nuclear attachment for motor-driven nucleokinesis in migrating neurons and interkinetic nuclear migration in neural progenitors, and it is required for centrosome migration during ciliogenesis. Shorter isoforms lacking the actin-binding or KASH domains localize to the inner nuclear membrane (where they bind lamin A and emerin), nucleoplasm, sarcoplasmic reticulum, sarcomeric Z-discs and focal adhesions. SYNE2 variants are associated with Emery-Dreifuss muscular dystrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003779 actin binding | ISS GO_REF:0000024 | ACCEPT | Summary: Actin binding (ISS); the N-terminal paired calponin-homology domains of giant nesprin-2 bind F-actin. Reason: Directly supported for the human protein: the NUANCE actin-binding domain binds F-actin in vitro and colocalizes with actin in cells. Supporting Evidence: PMID:12118075 Domain analysis shows that the actin-binding domain binds to Factin in vitro and colocalizes with the actin cytoskeleton in vivo as a GFP-fusion protein. |
| GO:0005515 protein binding | IPI PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | MODIFY | Summary: IPI with lamin A (LMNA); smaller nesprin-2 isoforms bind lamin A and emerin at the inner nuclear envelope. Reason: The paper reports specific binding to lamin A; GO:0005521 lamin binding is the informative replacement. This is a property of short isoforms and non-core. Proposed replacements: lamin binding Supporting Evidence: PMID:15671068 The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). |
| GO:0005515 protein binding | IPI PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | REMOVE | Summary: IPI with emerin (EMD) from the same study. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. No specific emerin-binding MF term applies. Supporting Evidence: PMID:15671068 The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). |
| GO:0005515 protein binding | IPI PMID:18396275 Structural requirements for the assembly of LINC complexes a... | REMOVE | Summary: IPI with SUN1; KASH2 binds luminal SUN domains. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:0005515 protein binding | IPI PMID:18396275 Structural requirements for the assembly of LINC complexes a... | REMOVE | Summary: IPI with SUN2; KASH2 binds luminal SUN domains. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:0005515 protein binding | IPI PMID:22555292 LINC complex alterations in DMD and EDMD/CMT fibroblasts. | REMOVE | Summary: IPI with SUN2 in patient fibroblasts with LINC complex alterations. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:22555292 SUN proteins together with the Nesprins form the core of the LINC complex which connects the nucleus with the cytoskeleton. |
| GO:0005515 protein binding | IPI PMID:22632968 LINC complexes form by binding of three KASH peptides to dom... | REMOVE | Summary: IPI with SUN2; crystal structure of the SUN2-KASH2 complex. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:22632968 Altogether 24 hydrogen bonds, 11 between SUN2 protomer 1 and KASH2, and 13 between protomer 2 and KASH2, tie the peptide strongly to the SUN2 trimer base. |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | REMOVE | Summary: IPI with APPL1 from a skeletal-muscle yeast two-hybrid interactome. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:23414517 A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome. |
| GO:0005515 protein binding | IPI PMID:24880667 FHOD1 interaction with nesprin-2G mediates TAN line formatio... | REMOVE | Summary: IPI with the formin FHOD1, which binds nesprin-2G spectrin repeats to reinforce TAN-line coupling to actin. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. The FHOD1 interaction is functionally important for TAN lines, but GO has no formin-binding MF; the resulting function is captured by nuclear migration along microfilament. Supporting Evidence: PMID:24880667 Here, we identify the diaphanous formin FHOD1 as an interaction partner of N2G. |
| GO:0005515 protein binding | IPI PMID:26506308 Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by ... | REMOVE | Summary: IPI with amphiphysin-2 (BIN1) in nuclear positioning. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:26506308 We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. |
| GO:0005515 protein binding | IPI PMID:28716842 Outer nuclear membrane protein Kuduk modulates the LINC comp... | REMOVE | Summary: IPI with TMEM258 (Kuduk homolog) via the KASH domain. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:28716842 Nesprin 1 and Nesprin 2 associated with TMEM258, but deletion of the KASH domain abolished this interaction. |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: High-throughput IPI with SUN2 from an interferon-stimulated-gene interactome. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:30833792 We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. |
| GO:0005515 protein binding | IPI PMID:33058875 Structural Analysis of Different LINC Complexes Reveals Dist... | REMOVE | Summary: IPI with SUN2 from structural analysis of LINC complexes. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:33058875 6xHis-GB1-KASH2 co-purified with both, SUN2 and GFP-KASH1. |
| GO:0005515 protein binding | IPI PMID:34818527 The ESCRT machinery counteracts Nesprin-2G-mediated mechanic... | REMOVE | Summary: IPI with the ESCRT-associated protein BROX, which binds nesprin-2G and promotes its ubiquitination at nuclear envelope rupture sites. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. Supporting Evidence: PMID:34818527 residues needed for binding to Nesprin-2G |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: High-throughput IPI with SUN2 from multimodal cell maps. Reason: Generic protein binding is uninformative. The interaction is not disputed, but binding alone does not specify a molecular function; the functionally relevant activity of nesprin-2 (linking the cytoskeleton to the nuclear membrane via SUN-KASH pairing) is captured by GO:0140444 and LINC complex membership. |
| GO:0005634 nucleus | IDA PMID:12118075 NUANCE, a giant protein connecting the nucleus and actin cyt... | KEEP AS NON CORE | Summary: Nucleus (IDA); NUANCE detected at the outer nuclear membrane and in the nucleoplasm. Reason: Supported for short soluble isoforms; the core location of giant nesprin-2 is the outer nuclear membrane. Supporting Evidence: PMID:12118075 At the subcellular level NUANCE is present predominantly at the outer nuclear membrane and in the nucleoplasm. file:human/SYNE2/SYNE2-uniprot.txt Shorter soluble isoforms can be found in the cytoplasm and within the nucleus. |
| GO:0005635 nuclear envelope | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | ACCEPT | Summary: Nuclear envelope (IDA). Reason: Nesprin-2 isoforms with the C-terminal KASH/transmembrane domain are anchored at the nuclear envelope. Supporting Evidence: PMID:15671068 detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. PMID:12118075 The C-terminal transmembrane domain is responsible for the targeting the nuclear envelope. |
| GO:0005640 nuclear outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear outer membrane (IEA from UniProt subcellular location). Reason: Core location: KASH-domain nesprin-2 is a tail-anchored outer nuclear membrane protein whose KASH peptide binds SUN proteins in the perinuclear space. Supporting Evidence: PMID:12118075 At the subcellular level NUANCE is present predominantly at the outer nuclear membrane and in the nucleoplasm. PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleoplasm (IEA). Reason: Applies to short soluble isoforms; non-core. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt Shorter soluble isoforms can be found in the cytoplasm and within the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:12118075 NUANCE, a giant protein connecting the nucleus and actin cyt... | KEEP AS NON CORE | Summary: Cytoplasm (IDA, NUANCE actin-binding domain colocalizes with actin). Reason: The large cytoplasmic domain of the ONM protein and short soluble isoforms are cytoplasmic; correct but non-specific. Supporting Evidence: PMID:12118075 Domain analysis shows that the actin-binding domain binds to Factin in vitro and colocalizes with the actin cytoskeleton in vivo as a GFP-fusion protein. file:human/SYNE2/SYNE2-uniprot.txt Shorter soluble isoforms can be found in the cytoplasm and within the nucleus. |
| GO:0005737 cytoplasm | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Cytoplasm (IDA, multiple cytoplasmic compartments). Reason: Correct but non-specific. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt Shorter soluble isoforms can be found in the cytoplasm and within the nucleus. |
| GO:0005739 mitochondrion | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Mitochondrion (IDA, immunogold EM). Reason: Reported with epitope-specific antibodies in one study; isoform identity and functional significance are unclear. Retained as a non-core, isoform-dependent location. Supporting Evidence: PMID:15671068 detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. file:human/SYNE2/SYNE2-deep-research-falcon.md These non-envelope localizations should not be generalized to every isoform. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrion (IEA from UniProt location). Reason: Derives from the same single immunolocalization study; non-core. Supporting Evidence: PMID:15671068 detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoskeleton (IEA). Reason: Giant nesprin-2 binds F-actin and, via BICD2, microtubule motors; correct though general. Supporting Evidence: PMID:12118075 Domain analysis shows that the actin-binding domain binds to Factin in vitro and colocalizes with the actin cytoskeleton in vivo as a GFP-fusion protein. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane (IEA). Reason: Some transmembrane isoforms are reported at plasma membrane foci; non-core. Supporting Evidence: PMID:15671068 detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. file:human/SYNE2/SYNE2-uniprot.txt The isoforms having the C-terminal transmembrane span can be found in several organellar membranes like the nuclear envelope, the sarcoplasmic reticulum of myoblasts, or the lamellipodia and focal adhesions at the cell membrane. |
| GO:0005925 focal adhesion | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Focal adhesion (IDA). Reason: Reported for small isoforms (e.g. p32CH/isoform 8); non-core. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt The isoforms having the C-terminal transmembrane span can be found in several organellar membranes like the nuclear envelope, the sarcoplasmic reticulum of myoblasts, or the lamellipodia and focal adhesions at the cell membrane. |
| GO:0005925 focal adhesion | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Focal adhesion (IEA). Reason: Isoform-dependent; non-core. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt The isoforms having the C-terminal transmembrane span can be found in several organellar membranes like the nuclear envelope, the sarcoplasmic reticulum of myoblasts, or the lamellipodia and focal adhesions at the cell membrane. |
| GO:0007097 nuclear migration | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear migration (IBA). Nesprin-2, as the outer-nuclear-membrane KASH protein of LINC complexes, couples the nucleus to actin (TAN lines) and to dynein/kinesin (via BICD2) to move and position the nucleus. Reason: Consistent with the PAINT node and with direct evidence in fibroblasts and neurons (including rescue with motor-binding-site mutants in cerebellar granule neurons). Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. PMID:32619477 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. PMID:39115447 we demonstrate that Nesprin-2 serves as a nucleus-motor adaptor, coordinating the interplay of kinesin-1 and dynein. PMID:39115447 Both motor binding sites are required to rescue nuclear migration defects caused by the loss of function of Nesprin-2. |
| GO:0007097 nuclear migration | IEA GO_REF:0000117 | ACCEPT | Summary: Nuclear migration (IEA ortholog transfer). Reason: Correct; see IBA and IMP rows. Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. |
| GO:0007097 nuclear migration | IMP PMID:20724637 Linear arrays of nuclear envelope proteins harness retrograd... | ACCEPT | Summary: Nuclear migration (IMP); nesprin-2G/SUN2 TAN lines harness retrograde actin flow to move the nucleus in polarizing fibroblasts. Reason: Direct experimental evidence of a core function. Supporting Evidence: PMID:20724637 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:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane (IEA, InterPro). Reason: Correct; KASH-containing isoforms are tail-anchored membrane proteins. Supporting Evidence: PMID:12118075 The C-terminal transmembrane domain is responsible for the targeting the nuclear envelope. |
| GO:0016529 sarcoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sarcoplasmic reticulum (IBA). Reason: Nesprin-2 isoforms localize to SR in muscle; tissue-specific, non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0016529 sarcoplasmic reticulum | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Sarcoplasmic reticulum (IDA). Reason: Tissue-specific isoform location; non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0030017 sarcomere | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sarcomere (IBA). Reason: Nesprin-2 isoforms relocalize to sarcomeres in differentiated muscle; non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0030018 Z disc | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Z disc (IDA). Reason: Muscle-specific isoform location; non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0030018 Z disc | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Z disc (IEA). Reason: Muscle-specific isoform location; non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0030335 positive regulation of cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of cell migration (ISS). Reason: Nesprin-2G-dependent nuclear movement and centrosome reorientation are needed for polarized fibroblast migration, so a role in migration is plausible, but it is an indirect consequence of nuclear positioning; non-core. Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. file:human/SYNE2/SYNE2-deep-research-falcon.md A phenotype from pan-SYNE2 knockdown cannot automatically be attributed to nesprin-2 giant |
| GO:0031022 nuclear migration along microfilament | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear migration along microfilament (ISS); nesprin-2G/SUN2 TAN lines couple the nucleus to retrogradely flowing dorsal actin cables. Reason: Directly supported by human-relevant nesprin-2G data; a core actin-dependent nuclear movement function. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. PMID:20724637 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. |
| GO:0031258 lamellipodium membrane | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Lamellipodium membrane (IDA). Reason: Isoform-dependent peripheral location noted in UniProt; non-core. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt The isoforms having the C-terminal transmembrane span can be found in several organellar membranes like the nuclear envelope, the sarcoplasmic reticulum of myoblasts, or the lamellipodia and focal adhesions at the cell membrane. file:human/SYNE2/SYNE2-deep-research-falcon.md These non-envelope localizations should not be generalized to every isoform. |
| GO:0031527 filopodium membrane | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Filopodium membrane (IDA). Reason: Isoform-dependent peripheral location; non-core. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt The isoforms having the C-terminal transmembrane span can be found in several organellar membranes like the nuclear envelope, the sarcoplasmic reticulum of myoblasts, or the lamellipodia and focal adhesions at the cell membrane. |
| GO:0031965 nuclear membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear membrane (IBA). Reason: Correct; the KASH domain anchors nesprin-2 in the nuclear envelope. Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:0031981 nuclear lumen | IDA PMID:15671068 Nesprin-2 is a multi-isomeric protein that binds lamin and e... | KEEP AS NON CORE | Summary: Nuclear lumen (IDA, intranuclear foci). Reason: Short isoforms; non-core. Supporting Evidence: PMID:15671068 detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. |
| GO:0033017 sarcoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Sarcoplasmic reticulum membrane (IEA). Reason: Tissue-specific isoform location; non-core. Supporting Evidence: PMID:15671068 nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IDA PMID:18396275 Structural requirements for the assembly of LINC complexes a... | MODIFY | Summary: Part of meiotic nuclear membrane microtubule tethering complex (IDA); KASH2 forms LINC complexes with SUN1/SUN2. Reason: Nesprin-2 is a core KASH component of LINC complexes, but the evidence is from somatic cells (HeLa/fibroblasts, structural reconstitution) and its functions (nuclear movement, mechanotransduction, neuronal nucleokinesis) are interphase somatic functions. GO:0034993 is the meiosis-specific child; the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is the appropriate term. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. PMID:18396275 These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IEA GO_REF:0000117 | MODIFY | Summary: Part of meiotic LINC complex (IEA ortholog transfer). Reason: Nesprin-2 is a core KASH component of LINC complexes, but the evidence is from somatic cells (HeLa/fibroblasts, structural reconstitution) and its functions (nuclear movement, mechanotransduction, neuronal nucleokinesis) are interphase somatic functions. GO:0034993 is the meiosis-specific child; the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is the appropriate term. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IPI PMID:22632968 LINC complexes form by binding of three KASH peptides to dom... | MODIFY | Summary: Part of meiotic LINC complex (IPI); SUN2-KASH2 heterohexamer structure. Reason: Nesprin-2 is a core KASH component of LINC complexes, but the evidence is from somatic cells (HeLa/fibroblasts, structural reconstitution) and its functions (nuclear movement, mechanotransduction, neuronal nucleokinesis) are interphase somatic functions. GO:0034993 is the meiosis-specific child; the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is the appropriate term. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:22632968 Altogether 24 hydrogen bonds, 11 between SUN2 protomer 1 and KASH2, and 13 between protomer 2 and KASH2, tie the peptide strongly to the SUN2 trimer base. |
| GO:0045111 intermediate filament cytoskeleton | IDA GO_REF:0000052 | UNDECIDED | Summary: Intermediate filament cytoskeleton (IDA, Human Protein Atlas immunofluorescence). Reason: The HPA image data are not available here to evaluate, and there is no known mechanism linking nesprin-2 to intermediate filaments (that role is attributed to nesprin-3 via plectin). Neither accepted nor removed. |
| GO:0051642 centrosome localization | IBA GO_REF:0000033 | ACCEPT | Summary: Centrosome localization (IBA). Reason: Nesprin-2 LINC complexes couple the nucleus to the centrosome: nuclear movement positions/reorients the centrosome in fibroblasts, and nesprin-2 is required for centrosome migration during ciliogenesis. Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. file:human/SYNE2/SYNE2-uniprot.txt Required for centrosome migration to the apical cell surface during early ciliogenesis. |
| GO:0051642 centrosome localization | IEA GO_REF:0000117 | ACCEPT | Summary: Centrosome localization (IEA ortholog transfer). Reason: As for IBA. Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. |
| GO:0051642 centrosome localization | IMP PMID:20724637 Linear arrays of nuclear envelope proteins harness retrograd... | ACCEPT | Summary: Centrosome localization (IMP); inhibition of nesprin-2G prevents nuclear movement and centrosome reorientation. Reason: Direct experimental evidence. Supporting Evidence: PMID:20724637 Inhibition of nesprin2G, SUN2, or actin prevented nuclear movement and centrosome reorientation. |
| GO:0070062 extracellular exosome | HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ... | MARK AS OVER ANNOTATED | Summary: Extracellular exosome (HDA, exosome proteomics). Reason: Detection of a fragment of this giant nuclear-envelope protein in exosome preparations by mass spectrometry does not indicate a functional exosomal location. Supporting Evidence: PMID:18570454 Exosomal lysates of each fraction were digested and analyzed using nanoflow LC-ESI-MS-MS for protein identification. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoskeleton-nuclear membrane anchor activity (IBA). Reason: Core molecular function: nesprin-2 bridges the cytoskeleton (F-actin via CH domains, dynein-dynactin via BICD2 and kinesin-1 via a LEWD motif) and the nuclear membrane (via KASH-SUN pairing). Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. file:human/SYNE2/SYNE2-uniprot.txt SYNE2 and SUN2 assemble in arrays of transmembrane actin-associated nuclear (TAN) lines which are bound to F-actin cables and couple the nucleus to retrograde actin flow during actin-dependent nuclear movement. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | IDA PMID:18396275 Structural requirements for the assembly of LINC complexes a... | ACCEPT | Summary: Cytoskeleton-nuclear membrane anchor activity (IDA); KASH2 binding to SUN proteins establishes LINC connections, and their disruption reduces cellular mechanical stiffness. Reason: Core molecular function: nesprin-2 bridges the cytoskeleton (F-actin via CH domains, dynein-dynactin via BICD2 and kinesin-1 via a LEWD motif) and the nuclear membrane (via KASH-SUN pairing). Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. PMID:18396275 These findings support a model whereby physical connections between the nucleus and the cytoskeleton are mediated by interactions between diverse combinations of Sun proteins and Nesprins through their respective evolutionary-conserved domains. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | IEA GO_REF:0000117 | ACCEPT | Summary: Cytoskeleton-nuclear membrane anchor activity (IEA ortholog transfer). Reason: Core molecular function: nesprin-2 bridges the cytoskeleton (F-actin via CH domains, dynein-dynactin via BICD2 and kinesin-1 via a LEWD motif) and the nuclear membrane (via KASH-SUN pairing). Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:1902017 regulation of cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of cilium assembly (IBA). Reason: Nesprin-2 is required for centrosome migration to the apical surface during early ciliogenesis; a context-specific consequence of nucleus-centrosome coupling rather than a core function. Supporting Evidence: file:human/SYNE2/SYNE2-uniprot.txt Required for centrosome migration to the apical cell surface during early ciliogenesis. |
| GO:0021817 nucleokinesis involved in cell motility in cerebral cortex radial glia guided migration | ISS PMID:32619477 Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Contr... | NEW | Summary: Nesprin-2 recruits dynein-dynactin (via BICD2) and kinesin-1 to the nuclear envelope of migrating neurons; disrupting this interaction severely inhibits nuclear movement while centrosome advance continues. Syne-2 loss in mouse likewise disrupts radial migration and interkinetic nuclear migration. Reason: Participation test: nesprin-2 does part of the work of nucleokinesis by providing the structural link through which motor force is applied to the nucleus (the scaffold/anchor case), not merely by being required. Comparator: other nuclear-envelope motor adaptors in this process (BICD2, SUN1/SUN2 are the analogous anchor-role proteins) carry nuclear migration terms; the specific nucleokinesis term is justified by rodent in vivo data transferred to the conserved human ortholog. Supporting Evidence: PMID:32619477 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. PMID:32619477 Although disruption of the Nesprin-2/BicD2 interaction severely inhibited nuclear movement, centrosome advance proceeded unimpeded, supporting an independent mechanism for centrosome advance. PMID:32619477 We find that an ∼100-kDa "mini" form of the ∼800-kDa Nesprin-2 protein, which binds dynein and kinesin, is sufficient, remarkably, to support neuronal migration. PMID:19874786 Our current study uncovers a somewhat surprising function of Syne-1 and Syne-2 in connecting the NE to the microtubule network during radial neuronal migration and interkinetic nuclear movement. PMID:39115447 Nesprin-2 recruits dynein-dynactin-BicD2 independently of the nearby kinesin-binding LEWD motif. PMID:39115447 Both motor binding sites are required to rescue nuclear migration defects caused by the loss of function of Nesprin-2. |
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Download this section (compressed HTML)Q: Should human SUN1/SUN2/SYNE1/SYNE2 annotations to GO:0034993 (meiotic LINC complex) be moved to the non-meiotic parent GO:0106094, given that nearly all supporting evidence is from interphase somatic cells?
Suggested experts: GO cellular component editors, nuclear envelope biologists
Q: Is the nesprin-2 cytoplasmic region that binds BICD2 (LEWD-like motif) conserved in nesprin-1, and do the two nesprins contribute redundantly to neuronal nucleokinesis in human cortex development?
Suggested experts: neuronal migration biologists
Q: Which nesprin-2 isoforms account for the reported mitochondrial, plasma-membrane and intermediate-filament localizations?
Suggested experts: nesprin isoform biologists, Human Protein Atlas curators
Experiment: Isoform-specific knockout or KASH-domain deletion of SYNE2 in human iPSC-derived cortical organoids with live imaging of neuronal nucleokinesis and interkinetic nuclear migration.
Hypothesis: KASH-containing nesprin-2 isoforms are required in human cortical progenitors and neurons for dynein-driven nuclear movement, with partial redundancy from nesprin-1.
Type: organoid live imaging
Experiment: Reconstitute SUN2-KASH2 LINC complexes with a mini-nesprin-2 carrying the BICD2-binding site in supported bilayers and measure dynein-dynactin-BICD2 force transmission with optical tweezers.
Hypothesis: The nesprin-2-BICD2 interaction is sufficient to transmit dynein pulling force to a membrane-anchored LINC complex.
Type: in vitro reconstitution/force spectroscopy
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