SYNE1 encodes nesprin-1, a family of spectrin-repeat proteins produced from a very large gene by alternative promoters and splicing. The giant isoform (enaptin, ~1 MDa) has paired N-terminal calponin-homology actin-binding domains, 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 (with a SUN-KASH disulfide) to form LINC (linker of nucleoskeleton and cytoskeleton) complexes, which connect the actin and microtubule cytoskeletons, and associated dynein-dynactin and kinesin-1 motors, to the nuclear lamina. Through this bridge nesprin-1 transmits force across the nuclear envelope and functions in nuclear anchorage and positioning (notably of myonuclei and synaptic nuclei), nuclear shape, centrosome-nucleus coupling, and, redundantly with nesprin-2, nuclear migration in developing brain. Shorter isoforms lacking the actin-binding domain (nesprin-1alpha/myne-1, beta) are enriched in muscle and associate with lamin A/C and emerin at the nuclear envelope, while other isoforms localize to the Golgi, sarcomeric Z-lines, or processing bodies. Biallelic SYNE1 loss-of-function causes autosomal recessive cerebellar ataxia (SCAR8/ARCA1); SYNE1 variants are also associated with Emery-Dreifuss muscular dystrophy 4 and myogenic arthrogryposis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000932 P-body | IDA PMID:24862572 Mammalian microtubule P-body dynamics are mediated by nespri... | KEEP AS NON CORE | Summary: P-body localization (IDA) of the short p50Nesp1 isoform. Reason: A 50 kDa nesprin-1 isoform localizes to P-bodies and links them to microtubules. This is an isoform-specific, non-nuclear-envelope role distinct from the LINC function of KASH-containing nesprin-1. Supporting Evidence: PMID:24862572 Here, we characterize p50(Nesp1), a 50-kD isoform that localizes to processing bodies PMID:24862572 interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: RNA binding from high-throughput mRNA interactome capture. Reason: Nesprin-1 has no known RNA-binding domain; recovery in a UV-crosslinking mRNA-interactome screen is not evidence of an RNA-binding function (its P-body partner interactions are RNA-dependent, i.e. indirect). Supporting Evidence: PMID:22658674 Employing two complementary protocols for covalent UV crosslinking of RBPs to RNA |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | MARK AS OVER ANNOTATED | Summary: RNA binding from high-throughput mRNA interactome capture. Reason: Nesprin-1 has no known RNA-binding domain; recovery in a UV-crosslinking mRNA-interactome screen is not evidence of an RNA-binding function (its P-body partner interactions are RNA-dependent, i.e. indirect). Supporting Evidence: PMID:22681889 We developed a photoreactive nucleotide-enhanced UV crosslinking and oligo(dT) purification approach to identify the mRNA-bound proteome |
| GO:0003779 actin binding | IDA PMID:12408964 The nesprins are giant actin-binding proteins, orthologous t... | ACCEPT | Summary: Actin binding via the paired N-terminal calponin-homology domains of giant nesprin-1. Reason: Giant nesprin-1 (enaptin) carries an N-terminal alpha-actinin-type CH-CH actin-binding domain; actin binding is the cytoskeleton-facing half of its LINC anchoring function. Supporting Evidence: PMID:12408964 We show that the previously described nesprins are short isoforms of giant proteins comprising an actin-binding amino-terminus connected to a carboxy-terminal klarsicht-related transmembrane domain file:human/SYNE1/SYNE1-uniprot.txt Interacts with F-actin |
| GO:0003779 actin binding | IEA GO_REF:0000117 | ACCEPT | Summary: Actin binding via the paired N-terminal calponin-homology domains of giant nesprin-1. Reason: Giant nesprin-1 (enaptin) carries an N-terminal alpha-actinin-type CH-CH actin-binding domain; actin binding is the cytoskeleton-facing half of its LINC anchoring function. Supporting Evidence: PMID:12408964 We show that the previously described nesprins are short isoforms of giant proteins comprising an actin-binding amino-terminus connected to a carboxy-terminal klarsicht-related transmembrane domain file:human/SYNE1/SYNE1-uniprot.txt Interacts with F-actin |
| GO:0005515 protein binding | IPI PMID:12812986 DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associa... | REMOVE | Summary: Protein binding (IPI) with DISC1. Reason: GO:0005515 protein binding is uninformative. DISC1 interaction from interaction screens/compilations; it does not identify a nesprin-1 molecular activity. Supporting Evidence: PMID:12812986 DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system |
| GO:0005515 protein binding | IPI Q8NF91-3 PMID:17462627 Distinct functional domains in nesprin-1alpha and nesprin-2b... | REMOVE | Summary: Protein binding (IPI) of nesprin-1alpha (isoform 3) to emerin. Reason: GO:0005515 protein binding is uninformative. Nesprin-1alpha spectrin repeats bind emerin and help retain it at the nuclear membrane; the interaction is real but no more informative MF term applies, and it is an isoform-specific inner-nuclear-membrane interaction. Supporting Evidence: PMID:17462627 residues 368 to 627 of nesprin-1alpha and residues 126 to 219 of nesprin-2beta, which show high homology to one another, both mediate binding to emerin residues 140-176. |
| GO:0005515 protein binding | IPI PMID:18396275 Structural requirements for the assembly of LINC complexes a... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. PMID:18396275 We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness |
| GO:0005515 protein binding | IPI PMID:18396275 Structural requirements for the assembly of LINC complexes a... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. PMID:18396275 We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness |
| GO:0005515 protein binding | IPI PMID:22632968 LINC complexes form by binding of three KASH peptides to dom... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:22632968 We present crystal structures of the human SUN2-KASH1/2 complex, the core of the LINC complex. PMID:22632968 Thereby, molecular tethers are formed that can transmit forces for chromosome movements, nuclear migration, and anchorage. |
| GO:0005515 protein binding | IPI PMID:22632968 LINC complexes form by binding of three KASH peptides to dom... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:22632968 We present crystal structures of the human SUN2-KASH1/2 complex, the core of the LINC complex. PMID:22632968 Thereby, molecular tethers are formed that can transmit forces for chromosome movements, nuclear migration, and anchorage. |
| GO:0005515 protein binding | IPI PMID:28716842 Outer nuclear membrane protein Kuduk modulates the LINC comp... | REMOVE | Summary: Protein binding (IPI) to TMEM258 (Kuduk orthologue), KASH-dependent. Reason: GO:0005515 protein binding is uninformative. Co-immunoprecipitation with TMEM258 in overexpressing 293T cells; the functional meaning (LINC quality control) is established in Drosophila and does not define a nesprin-1 molecular activity. 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:31413325 HENA, heterogeneous network-based data set for Alzheimer's d... | REMOVE | Summary: Protein binding (IPI) with DISC1. Reason: GO:0005515 protein binding is uninformative. DISC1 interaction from interaction screens/compilations; it does not identify a nesprin-1 molecular activity. |
| GO:0005515 protein binding | IPI PMID:33058875 Structural Analysis of Different LINC Complexes Reveals Dist... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33058875 Finally, a disulfide bond can be formed between SUN2 C563 and KASH1 C8774 or KASH2 C6862 via highly conserved cysteine residues. PMID:33058875 They transmit mechanical force across the NE in processes such as nuclear anchorage, nuclear migration, and homologous chromosome pairing during meiosis. |
| GO:0005515 protein binding | IPI PMID:33393904 A molecular mechanism for LINC complex branching by structur... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33393904 We next solved the crystal structure of the SUN-KASH complex between SUN1 and Nesprin-1 (herein referred to as SUN1-KASH1). PMID:33393904 We find that SUN-KASH complexes between SUN proteins and Nesprin-4, KASH5 and Nesprin-1 are 6:6 structures formed of constitutive interactions between two 3:3 complexes. |
| GO:0005515 protein binding | IPI PMID:33393904 A molecular mechanism for LINC complex branching by structur... | MODIFY | Summary: Protein binding (IPI) to SUN1/SUN2 via the KASH domain. Reason: GO:0005515 protein binding is uninformative. The interaction reported here is the SUN-KASH binding that forms the LINC complex bridge across the perinuclear space, which is the molecular basis of nesprin-1 anchoring the cytoskeleton to the nuclear envelope. The informative MF is cytoskeleton-nuclear membrane anchor activity (with part_of LINC complex). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33393904 We next solved the crystal structure of the SUN-KASH complex between SUN1 and Nesprin-1 (herein referred to as SUN1-KASH1). PMID:33393904 We find that SUN-KASH complexes between SUN proteins and Nesprin-4, KASH5 and Nesprin-1 are 6:6 structures formed of constitutive interactions between two 3:3 complexes. |
| GO:0005521 lamin binding | IPI PMID:11801724 Myne-1, a spectrin repeat transmembrane protein of the myocy... | KEEP AS NON CORE | Summary: Lamin binding (IPI): the muscle short isoform myne-1 co-immunoprecipitates with lamin A/C. Reason: Shown for the inner-nuclear-membrane short isoform myne-1 in differentiated muscle; the giant KASH isoforms connect to the lamina indirectly through SUN proteins. Retained as an isoform-specific, non-core activity. Supporting Evidence: PMID:11801724 we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. PMID:11801724 We have identified a protein of the inner nuclear membrane that is highly expressed in striated and smooth muscle. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | KEEP AS NON CORE | Summary: Nucleus (HDA) from human sperm-nucleus proteomics. Reason: Nesprin-1 is a nuclear-envelope protein and a SUN3-SYNE1 complex is proposed in spermatid head shaping, so co-purification with sperm nuclei is plausible, but this is a high-throughput location that adds little. Supporting Evidence: PMID:21630459 With this approach, 403 different proteins have been identified from the isolated sperm nuclei. file:human/SYNE1/SYNE1-uniprot.txt a probable SUN3:SYNE1/KASH1 LINC complex may tether spermatid nuclei to posterior cytoskeletal structures such as the manchette. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus (IEA, UniProt subcellular location). Reason: Short nesprin-1 isoforms and nesprin-1 in differentiating myoblasts are found inside the nucleus; the principal functional site of KASH-containing nesprin-1 is the nuclear envelope. Supporting Evidence: PMID:11792814 immunogold labeling confirmed its presence at the nuclear envelope and in the nucleus where it colocalized with heterochromatin. file:human/SYNE1/SYNE1-uniprot.txt In myoblasts, relocalized from the nuclear envelope to the nucleus and cytoplasm during cell differentiation. |
| GO:0005635 nuclear envelope | IDA PMID:11792814 Nesprins: a novel family of spectrin-repeat-containing prote... | ACCEPT | Summary: Nuclear envelope / nuclear membrane localization. Reason: KASH-containing nesprin-1 is a tail-anchored nuclear envelope protein retained there by SUN binding. Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:0005635 nuclear envelope | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear envelope / nuclear membrane localization. Reason: KASH-containing nesprin-1 is a tail-anchored nuclear envelope protein retained there by SUN binding. Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:0005640 nuclear outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear outer membrane (IEA). Reason: The KASH transmembrane segment anchors giant nesprin-1 in the outer nuclear membrane with its bulk cytoplasmic; this is the principal functional location. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Nucleus outer membrane file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Nucleoplasm (IDA, Human Protein Atlas immunofluorescence). Reason: Intranuclear nesprin-1 immunostaining has been reported (short isoforms, differentiating myoblasts), but is secondary to the nuclear envelope location; antibody-based detection cannot resolve isoforms. Supporting Evidence: PMID:11792814 immunogold labeling confirmed its presence at the nuclear envelope and in the nucleus where it colocalized with heterochromatin. |
| GO:0005730 nucleolus | IDA PMID:24862572 Mammalian microtubule P-body dynamics are mediated by nespri... | UNDECIDED | Summary: Nucleolus (IDA) from a paper on the p50Nesp1 P-body isoform; abstract-only cache. Reason: The cached abstract describes P-body localization of p50Nesp1 and does not mention nucleolar localization; without the full text the basis for a nucleolar annotation cannot be judged. Supporting Evidence: PMID:24862572 Here, we characterize p50(Nesp1), a 50-kD isoform that localizes to processing bodies |
| GO:0005737 cytoplasm | IDA PMID:11792814 Nesprins: a novel family of spectrin-repeat-containing prote... | KEEP AS NON CORE | Summary: Cytoplasm (IDA). Reason: Most of giant nesprin-1 projects into the cytoplasm and nesprin-1 relocalizes to the cytoplasm during myoblast differentiation; correct but generic. Supporting Evidence: PMID:11792814 Nesprin-1 is developmentally regulated in both smooth and skeletal muscle and is re-localized from the nuclear envelope to the nucleus and cytoplasm during C2C12 myoblast differentiation. file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. |
| GO:0005794 Golgi apparatus | IDA PMID:12808039 Golgi localization of Syne-1. | KEEP AS NON CORE | Summary: Golgi apparatus. Reason: Specific nesprin-1 (Syne-1B/GSRP-56) isoforms or fragments localize to the Golgi; this is an isoform-specific, non-LINC location. Supporting Evidence: PMID:12808039 Golgi localization for this spectrin-like protein was demonstrated by expression of epitope-tagged fragments in MDBK and COS cells file:human/SYNE1/SYNE1-uniprot.txt [Isoform GSRP-56]: Golgi apparatus |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi apparatus. Reason: Specific nesprin-1 (Syne-1B/GSRP-56) isoforms or fragments localize to the Golgi; this is an isoform-specific, non-LINC location. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt [Isoform GSRP-56]: Golgi apparatus |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoskeleton (IEA). Reason: Giant nesprin-1 binds actin and is found at sarcomeric Z-lines; appropriate general location for its cytoskeletal-linking domain. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Interacts with F-actin PMID:12408964 the larger isoforms of nesprin-1, like MSP-300, are localized to the sarcomeric Z-line of both skeletal and cardiac muscle. |
| GO:0006997 nucleus organization | NAS PMID:11792814 Nesprins: a novel family of spectrin-repeat-containing prote... | ACCEPT | Summary: Nucleus organization (NAS). Reason: Nesprin-1-containing LINC complexes maintain nuclear shape and structural integrity; loss increases nuclear roundness in myotubes. Supporting Evidence: PMID:11792814 nesprins may function as 'dystrophins of the nucleus' to maintain nuclear organization and structural integrity. file:human/SYNE1/SYNE1-uniprot.txt The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. file:human/SYNE1/SYNE1-deep-research-falcon.md In differentiated C2C12 myotubes, nesprin-1 depletion removed nuclear-envelope-associated pericentrin and increased nuclear roundness. |
| GO:0007030 Golgi organization | IDA PMID:12808039 Golgi localization of Syne-1. | KEEP AS NON CORE | Summary: Golgi organization (IDA): a Golgi-binding fragment acts as a dominant negative that collapses the Golgi. Reason: Evidence is from over-expression of a dominant-negative fragment of a Golgi-associated isoform, which supports an isoform-specific contribution to Golgi structure but not a core function. Supporting Evidence: PMID:12808039 One of the Golgi binding domains on Syne-1 acts as a dominant negative inhibitor that alters the structure of the Golgi complex |
| GO:0007097 nuclear migration | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear migration (IBA). Reason: As the KASH half of the LINC complex, nesprin-1 transmits cytoskeletal motor forces to the nucleus: it is required for myonuclear anchorage/positioning and acts redundantly with nesprin-2 in neuronal nuclear migration in hindbrain/cerebellum regions. Supporting Evidence: PMID:19874786 We report here that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. PMID:19874786 Syne-1 and Syne-2 act redundantly in the midbrain, the cerebellum and the hindbrain PMID:19874786 We and others have previously shown that the KASH protein Syne-1/Nesprin-1 and Lamin A/C are essential for the anchorage of synaptic and non-synaptic nuclei of skeletal muscle cells in mice file:human/SYNE1/SYNE1-uniprot.txt The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. file:human/SYNE1/SYNE1-deep-research-falcon.md In mouse cardiomyocytes, disruption of the nesprin-1 KASH domain removed microtubule-associated elements from the nuclear envelope and reduced internuclear spacing. |
| GO:0016020 membrane | IDA PMID:11792814 Nesprins: a novel family of spectrin-repeat-containing prote... | ACCEPT | Summary: Membrane. Reason: Nesprin-1 KASH isoforms are tail-anchored integral membrane proteins; correct but general (nuclear outer membrane is the specific location). Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt Nucleus outer membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane. Reason: Nesprin-1 KASH isoforms are tail-anchored integral membrane proteins; correct but general (nuclear outer membrane is the specific location). Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt Nucleus outer membrane |
| GO:0016529 sarcoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sarcoplasmic reticulum (IBA). Reason: The outer nuclear membrane is continuous with the ER/SR, and nesprin-1 accumulates in ER/SR membranes when SUN binding is lost; muscle nesprin-1 isoforms may also reside in SR. Plausible but not the principal functional location. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. |
| GO:0019899 enzyme binding | IPI PMID:24862572 Mammalian microtubule P-body dynamics are mediated by nespri... | MARK AS OVER ANNOTATED | Summary: Enzyme binding (IPI) with P-body components (AGO2, DDX6/Rck, DCP1A) for the p50Nesp1 isoform. Reason: The abstract states that the interaction with Ago2 and Rck/p54 is RNA-dependent, i.e. bridged by RNA rather than direct binding; the generic term enzyme binding overstates a direct molecular activity for an isoform-specific P-body scaffold role. Supporting Evidence: PMID:24862572 interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. |
| GO:0019899 enzyme binding | IPI PMID:24862572 Mammalian microtubule P-body dynamics are mediated by nespri... | MARK AS OVER ANNOTATED | Summary: Enzyme binding (IPI) with P-body components (AGO2, DDX6/Rck, DCP1A) for the p50Nesp1 isoform. Reason: The abstract states that the interaction with Ago2 and Rck/p54 is RNA-dependent, i.e. bridged by RNA rather than direct binding; the generic term enzyme binding overstates a direct molecular activity for an isoform-specific P-body scaffold role. Supporting Evidence: PMID:24862572 interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. |
| GO:0019899 enzyme binding | IPI PMID:24862572 Mammalian microtubule P-body dynamics are mediated by nespri... | MARK AS OVER ANNOTATED | Summary: Enzyme binding (IPI) with P-body components (AGO2, DDX6/Rck, DCP1A) for the p50Nesp1 isoform. Reason: The abstract states that the interaction with Ago2 and Rck/p54 is RNA-dependent, i.e. bridged by RNA rather than direct binding; the generic term enzyme binding overstates a direct molecular activity for an isoform-specific P-body scaffold role. Supporting Evidence: PMID:24862572 interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. |
| GO:0030017 sarcomere | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sarcomere localization. Reason: Large nesprin-1 isoforms localize to the sarcomeric Z-line in skeletal and cardiac muscle; a real muscle-specific location but secondary to the nuclear-envelope LINC function. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt In skeletal and smooth muscles, a significant amount is found in the sarcomeres. |
| GO:0030017 sarcomere | IDA PMID:12408964 The nesprins are giant actin-binding proteins, orthologous t... | KEEP AS NON CORE | Summary: Sarcomere localization. Reason: Large nesprin-1 isoforms localize to the sarcomeric Z-line in skeletal and cardiac muscle; a real muscle-specific location but secondary to the nuclear-envelope LINC function. Supporting Evidence: PMID:12408964 the larger isoforms of nesprin-1, like MSP-300, are localized to the sarcomeric Z-line of both skeletal and cardiac muscle. file:human/SYNE1/SYNE1-uniprot.txt In skeletal and smooth muscles, a significant amount is found in the sarcomeres. |
| GO:0030017 sarcomere | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Sarcomere localization. Reason: Large nesprin-1 isoforms localize to the sarcomeric Z-line in skeletal and cardiac muscle; a real muscle-specific location but secondary to the nuclear-envelope LINC function. Supporting Evidence: PMID:12408964 the larger isoforms of nesprin-1, like MSP-300, are localized to the sarcomeric Z-line of both skeletal and cardiac muscle. file:human/SYNE1/SYNE1-uniprot.txt In skeletal and smooth muscles, a significant amount is found in the sarcomeres. |
| GO:0031965 nuclear membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear envelope / nuclear membrane localization. Reason: KASH-containing nesprin-1 is a tail-anchored nuclear envelope protein retained there by SUN binding. Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Nuclear envelope / nuclear membrane localization. Reason: KASH-containing nesprin-1 is a tail-anchored nuclear envelope protein retained there by SUN binding. Supporting Evidence: PMID:11792814 Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. file:human/SYNE1/SYNE1-uniprot.txt The largest part of the protein is cytoplasmic, while its C-terminal part is associated with the nuclear envelope, most probably the outer nuclear membrane. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IDA PMID:18396275 Structural requirements for the assembly of LINC complexes a... | MODIFY | Summary: Meiotic nuclear membrane microtubule tethering complex (LINC complex). Reason: Nesprin-1 is a core KASH component of LINC complexes with SUN1/SUN2, but the evidence (somatic HeLa/fibroblast LINC disruption and SUN-KASH1 crystal structures) is not meiosis-specific, and nesprin-1 functions in interphase somatic cells (myonuclear anchorage, nuclear migration). The meiosis-specific child term is too narrow; the general nuclear membrane microtubule tethering complex term is appropriate. 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. file:human/SYNE1/SYNE1-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 | IEA GO_REF:0000117 | MODIFY | Summary: Meiotic nuclear membrane microtubule tethering complex (LINC complex). Reason: Nesprin-1 is a core KASH component of LINC complexes with SUN1/SUN2, but the evidence (somatic HeLa/fibroblast LINC disruption and SUN-KASH1 crystal structures) is not meiosis-specific, and nesprin-1 functions in interphase somatic cells (myonuclear anchorage, nuclear migration). The meiosis-specific child term is too narrow; the general nuclear membrane microtubule tethering complex term is appropriate. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt the homotrimeric cloverleave-like conformation of the SUN domain is a prerequisite for LINC complex formation in which three separate SYNE1/KASH1 peptides bind at the interface of adjacent SUN domains. file:human/SYNE1/SYNE1-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: Meiotic nuclear membrane microtubule tethering complex (LINC complex). Reason: Nesprin-1 is a core KASH component of LINC complexes with SUN1/SUN2, but the evidence (somatic HeLa/fibroblast LINC disruption and SUN-KASH1 crystal structures) is not meiosis-specific, and nesprin-1 functions in interphase somatic cells (myonuclear anchorage, nuclear migration). The meiosis-specific child term is too narrow; the general nuclear membrane microtubule tethering complex term is appropriate. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:22632968 We present crystal structures of the human SUN2-KASH1/2 complex, the core of the LINC complex. file:human/SYNE1/SYNE1-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:33393904 A molecular mechanism for LINC complex branching by structur... | MODIFY | Summary: Meiotic nuclear membrane microtubule tethering complex (LINC complex). Reason: Nesprin-1 is a core KASH component of LINC complexes with SUN1/SUN2, but the evidence (somatic HeLa/fibroblast LINC disruption and SUN-KASH1 crystal structures) is not meiosis-specific, and nesprin-1 functions in interphase somatic cells (myonuclear anchorage, nuclear migration). The meiosis-specific child term is too narrow; the general nuclear membrane microtubule tethering complex term is appropriate. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:33393904 We next solved the crystal structure of the SUN-KASH complex between SUN1 and Nesprin-1 (herein referred to as SUN1-KASH1). file:human/SYNE1/SYNE1-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:0042692 muscle cell differentiation | IDA PMID:11792814 Nesprins: a novel family of spectrin-repeat-containing prote... | MARK AS OVER ANNOTATED | Summary: Muscle cell differentiation (IDA). Reason: The paper documents developmental regulation and relocalization of nesprin-1 during C2C12 differentiation, i.e. an expression/localization change, not a demonstrated role in executing muscle differentiation. Supporting Evidence: PMID:11792814 Nesprin-1 is developmentally regulated in both smooth and skeletal muscle and is re-localized from the nuclear envelope to the nucleus and cytoplasm during C2C12 myoblast differentiation. |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Self-association / homodimerization (projected from mouse). Reason: UniProt records self-association by similarity; spectrin-repeat rods can self-associate, and KASH peptides assemble in 3:3/6:6 SUN-KASH arrays, but homodimerization is not an established core activity of human nesprin-1. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Self-associates. |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Self-association / homodimerization (projected from mouse). Reason: UniProt records self-association by similarity; spectrin-repeat rods can self-associate, and KASH peptides assemble in 3:3/6:6 SUN-KASH arrays, but homodimerization is not an established core activity of human nesprin-1. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Self-associates. |
| GO:0045211 postsynaptic membrane | IDA PMID:10878022 Syne-1, a dystrophin- and Klarsicht-related protein associat... | MARK AS OVER ANNOTATED | Summary: Postsynaptic membrane (IDA) from the original Syne-1 description (abstract-only cache). Reason: The abstract localizes Syne-1 to the nuclear envelope of subsynaptic myonuclei lying beneath the postsynaptic membrane, rather than to the postsynaptic membrane itself. The annotation likely over-reads NMJ-enriched staining; the relevant location is the nuclear envelope of synaptic nuclei. Supporting Evidence: PMID:10878022 In adult skeletal muscle fibers, levels of Syne-1 are highest in the nuclei that lie beneath the postsynaptic membrane at the neuromuscular junction. PMID:10878022 We describe a novel protein, Syne-1, that is associated with nuclear envelopes in skeletal, cardiac, and smooth muscle cells. |
| GO:0051015 actin filament binding | ISS GO_REF:0000024 | ACCEPT | Summary: Actin filament binding (ISS from mouse). Reason: The N-terminal CH domains bind F-actin. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Interacts with F-actin PMID:12408964 We show that the previously described nesprins are short isoforms of giant proteins comprising an actin-binding amino-terminus connected to a carboxy-terminal klarsicht-related transmembrane domain |
| GO:0051642 centrosome localization | IBA GO_REF:0000033 | ACCEPT | Summary: Centrosome localization (IBA). Reason: Nesprin-1/2 LINC complexes couple the centrosome to the nucleus in neural progenitors and neurons and are required for centrosome migration during early ciliogenesis. Supporting Evidence: PMID:19874786 In Sun1/2 DKO and Syne-1/2 DKD glia cells, the distance between the centrosome and the nucleus was drastically increased compared to that in wild-type and heterozygous controls file:human/SYNE1/SYNE1-uniprot.txt Required for centrosome migration to the apical cell surface during early ciliogenesis. |
| GO:0090292 nuclear matrix anchoring at nuclear membrane | IDA PMID:11801724 Myne-1, a spectrin repeat transmembrane protein of the myocy... | KEEP AS NON CORE | Summary: Nuclear matrix anchoring at nuclear membrane (IDA): myne-1/lamin A/C association. Reason: Myne-1 (a short inner-nuclear-membrane isoform) colocalizes and co-precipitates with lamin A/C; the giant isoforms link the lamina to the cytoskeleton indirectly via SUN proteins. Plausible isoform-specific role. Supporting Evidence: PMID:11801724 we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoskeleton-nuclear membrane anchor activity. Reason: This is the core molecular function of KASH-containing nesprin-1: its N-terminal CH domains (and spectrin-repeat partners) engage the cytoskeleton while the luminal KASH peptide binds SUN proteins, anchoring the cytoskeleton to the nuclear envelope and transmitting force across it. Supporting Evidence: file:human/SYNE1/SYNE1-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. file:human/SYNE1/SYNE1-uniprot.txt The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| 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. Reason: This is the core molecular function of KASH-containing nesprin-1: its N-terminal CH domains (and spectrin-repeat partners) engage the cytoskeleton while the luminal KASH peptide binds SUN proteins, anchoring the cytoskeleton to the nuclear envelope and transmitting force across it. Supporting Evidence: PMID:18396275 the KASH domains of Nesprins 1, 2 and 3 interact promiscuously with luminal domains of Sun1 and Sun2. PMID:18396275 We demonstrate that the disruption of endogenous LINC complexes affect cellular mechanical stiffness file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | IEA GO_REF:0000117 | ACCEPT | Summary: Cytoskeleton-nuclear membrane anchor activity. Reason: This is the core molecular function of KASH-containing nesprin-1: its N-terminal CH domains (and spectrin-repeat partners) engage the cytoskeleton while the luminal KASH peptide binds SUN proteins, anchoring the cytoskeleton to the nuclear envelope and transmitting force across it. Supporting Evidence: file:human/SYNE1/SYNE1-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. file:human/SYNE1/SYNE1-uniprot.txt The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains. |
| GO:1902017 regulation of cilium assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of cilium assembly (IBA). Reason: Nesprin-1/2 are required for centrosome migration to the apical surface during early ciliogenesis (mouse/by similarity); the role in ciliogenesis is an indirect consequence of centrosome-nucleus positioning. Supporting Evidence: file:human/SYNE1/SYNE1-uniprot.txt Required for centrosome migration to the apical cell surface during early ciliogenesis. |
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Download this section (compressed HTML)Q: Which nesprin-1 isoforms directly recruit dynein-dynactin (via BICD2 or other adaptors) or kinesin-1 in migrating neurons, as opposed to nesprin-2 whose motor recruitment is better defined?
Q: Is the nucleolar localization of nesprin-1 (IDA from the p50Nesp1 paper) reproducible and isoform-specific?
Experiment: Isoform-selective (KASH-deletion vs CH-domain deletion) nesprin-1 alleles in hindbrain/cerebellar neurons on a nesprin-2 null background, with live imaging of nucleus-centrosome coupling to separate actin- versus microtubule-motor-coupled nuclear migration.
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