SYNE4 encodes nesprin-4, a 404-residue member of the nesprin (KASH-domain) family. It has a cytoplasmic region containing a coiled-coil, a single spectrin repeat and a kinesin-1-binding region, followed by a C-terminal transmembrane KASH domain that anchors it as a tail-anchored protein in the outer nuclear membrane. In the perinuclear space the KASH peptide binds the SUN domains of SUN1 and SUN2; nesprin-4 KASH forms 6:6 SUN-KASH assemblies in which opposing KASH4 chains coordinate zinc through a conserved CCSH motif, and its nuclear envelope localization depends on SUN1. On the cytoplasmic face nesprin-4 binds kinesin-1 (KIF5B/kinesin light chain) through a conserved LEWD motif, acting as a nuclear envelope cargo adaptor that couples the nucleus to plus-end-directed microtubule motor activity. Ectopic expression relocates the centrosome and Golgi apparatus relative to the nucleus in a kinesin-dependent manner. Nesprin-4 is expressed mainly in secretory epithelia and in cochlear hair cells, where a nesprin-4-SUN1 LINC complex keeps outer hair cell nuclei at the base of the cell; in its absence the nuclei move apically and the outer hair cells degenerate after the onset of hearing, and wild-type but not LEWD-mutant nesprin-4 delivered by AAV restores nuclear position and hearing in knockout mice. Homozygous truncating SYNE4 variants that fail to localize to the outer nuclear membrane cause progressive high-frequency hearing loss (DFNB76).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9BXN2. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:21516116 We describe a massively parallel interactome-mapping pipeline, Stitch-seq, that combines PCR stitching with next-generation sequencing and used it to generate a new human interactome dataset. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:A8K660. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:O00631. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:O75355. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:O95471. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:O95858. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:P11686. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:P15622-3. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:P54849. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:P56748. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:P56851. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q07325. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q08722. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q12893. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q13021. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q15437. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q16625. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q53G59. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q5BVD1. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q5J5C9. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q5TAB7. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q6PL45. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q6UX06. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q6ZP80. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q86UP2. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q86WT6. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q8N6G5. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q8TBU1. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q969F0. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q96D05. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q96DZ9. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q96E93. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q96IW7. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q96LK0. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9BVK8. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9BXN2. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9HC62. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9NRQ5. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9NRS4-3. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Nesprin-4 interacts with the kinesin light chain KLC4 (yeast two-hybrid). Reason: Generic protein binding is uninformative, but the partner is a kinesin-1 light chain and the interaction is observed independently by binary (Y2H) and co-complex (AP-MS) screens. It matches the established function of nesprin-4 as a kinesin-1 cargo adaptor at the nuclear envelope (binding KIF5B/KLC1 through a LEWD motif of the type that binds kinesin light chain TPR domains), so GO:0019894 kinesin binding is the evidence-backed informative replacement. Proposed replacements: kinesin binding Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. PMID:36211453 Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. PMID:36211453 A 4-amino acid motif that mediates binding to the TPR domain of the light chain of kinesin-1 in proteins file:human/SYNE4/SYNE4-uniprot.txt Interacts with kinesins KIF5B and KLC1 (By similarity). |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9NV12. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9NWD8. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9NXK6. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9P0N8. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9UEU0. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9ULW3. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9Y287. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q9UEU0. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:31515488 we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:33058875 Structural Analysis of Different LINC Complexes Reveals Dist... | MODIFY | Summary: Crystal structure of the human SUN2 SUN domain bound to the nesprin-4 KASH peptide (KASH4, residues 377-404). Reason: Direct structural evidence of KASH-SUN binding between nesprin-4 and SUN2. Generic protein binding is uninformative; SUN-KASH pairing is the mechanism by which nesprin-4 is anchored in the outer nuclear membrane and transmits kinesin-1 forces to the nucleus, so GO:0140444 cytoskeleton-nuclear membrane anchor activity is the informative replacement (consistent with the SUN1/SUN2 reviews). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33058875 We solved high-resolution crystal structures of SUN2522-717 in complex with KASH3948-975, KASH4377-404, and KASH5542-562, which complement our previously published SUN2-KASH1 and SUN2-KASH2 complexes. PMID:33058875 Similarly, 6xHis-GB1-KASH4 co-purified with SUN2 and GFP-KASH3. |
| GO:0005515 protein binding | IPI PMID:33393904 A molecular mechanism for LINC complex branching by structur... | MODIFY | Summary: Crystal structure and solution biophysics show SUN1 and the nesprin-4 KASH domain form a 6:6 SUN-KASH assembly stabilized by KASH4 zinc coordination. Reason: Direct structural evidence of KASH-SUN binding between nesprin-4 and SUN1. Generic protein binding is uninformative; SUN-KASH pairing is the mechanism by which nesprin-4 is anchored in the outer nuclear membrane and transmits kinesin-1 forces to the nucleus, so GO:0140444 cytoskeleton-nuclear membrane anchor activity is the informative replacement (consistent with the SUN1/SUN2 reviews). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33393904 A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. PMID:33393904 SUN1-KASH4, SUN1-KASH5, and SUN1-KASH1 form 6:6 complexes in solution, with experimental molecular weights of 150, 154, and 156 kDa, respectively |
| GO:0005515 protein binding | IPI PMID:33393904 A molecular mechanism for LINC complex branching by structur... | MODIFY | Summary: Crystal structure and solution biophysics show SUN2 and the nesprin-4 KASH domain form a 6:6 SUN-KASH assembly stabilized by KASH4 zinc coordination. Reason: Direct structural evidence of KASH-SUN binding between nesprin-4 and SUN2. Generic protein binding is uninformative; SUN-KASH pairing is the mechanism by which nesprin-4 is anchored in the outer nuclear membrane and transmits kinesin-1 forces to the nucleus, so GO:0140444 cytoskeleton-nuclear membrane anchor activity is the informative replacement (consistent with the SUN1/SUN2 reviews). Proposed replacements: cytoskeleton-nuclear membrane anchor activity Supporting Evidence: PMID:33393904 A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. PMID:33393904 SUN2-KASH4 was stable during purification (Figure 5a) and SEC-MALS analysis confirmed that it constitutes a 6:6 hetero-oligomer (Figure 5b). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q16625. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interaction of nesprin-4 with UniProtKB:Q8N6G5. Reason: Generic protein binding is uninformative. This partner comes from a high-throughput interactome screen; nesprin-4 is a small tail-anchored membrane protein, and its many binary hits with unrelated membrane proteins (claudins, tetraspanins, other small transmembrane proteins) do not point to any specific molecular function and are not supported by focused studies. Removal does not assert that the interaction is false. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Nesprin-4 interacts with the kinesin light chain KLC4 (affinity-purification mass spectrometry). Reason: Generic protein binding is uninformative, but the partner is a kinesin-1 light chain and the interaction is observed independently by binary (Y2H) and co-complex (AP-MS) screens. It matches the established function of nesprin-4 as a kinesin-1 cargo adaptor at the nuclear envelope (binding KIF5B/KLC1 through a LEWD motif of the type that binds kinesin light chain TPR domains), so GO:0019894 kinesin binding is the evidence-backed informative replacement. Proposed replacements: kinesin binding Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. PMID:36211453 Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. PMID:36211453 A 4-amino acid motif that mediates binding to the TPR domain of the light chain of kinesin-1 in proteins file:human/SYNE4/SYNE4-uniprot.txt Interacts with kinesins KIF5B and KLC1 (By similarity). |
| GO:0005635 nuclear envelope | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation (ARBA/InterPro SYNE4 family) to nuclear envelope. Reason: Correct; nesprin-4 is a KASH-anchored nuclear envelope protein (outer nuclear membrane). Supporting Evidence: PMID:23348741 As we report, nesprin-4 and Sun1 are both expressed in mechanosensory hair cells, where they localize primarily to the NE. PMID:23348741 Full-length nesprin-4 localizes to the NE, whereas both mutant proteins were found throughout the cytoplasm (Figure 2 C). |
| GO:0005640 nuclear outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference (PAINT node, mouse Syne4 donor) of outer nuclear membrane activity. Reason: Core location: the C-terminal transmembrane KASH domain anchors nesprin-4 in the outer nuclear membrane in a SUN-dependent manner, with its kinesin-binding N-terminal region in the cytoplasm; nesprin-4 localizes to the nuclear envelope of hair cells and truncating DFNB76 mutants lose this localization. Supporting Evidence: PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. PMID:23348741 SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. file:human/SYNE4/SYNE4-uniprot.txt Localization at the nucleus outer membrane requires the presence of SUN1. |
| GO:0005640 nuclear outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Ortholog/UniProt subcellular location based annotation to nuclear outer membrane. Reason: Core location: the C-terminal transmembrane KASH domain anchors nesprin-4 in the outer nuclear membrane in a SUN-dependent manner, with its kinesin-binding N-terminal region in the cytoplasm; nesprin-4 localizes to the nuclear envelope of hair cells and truncating DFNB76 mutants lose this localization. Supporting Evidence: PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. PMID:23348741 SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. file:human/SYNE4/SYNE4-uniprot.txt Localization at the nucleus outer membrane requires the presence of SUN1. |
| GO:0005640 nuclear outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse nesprin-4, an outer nuclear membrane protein. Reason: Core location: the C-terminal transmembrane KASH domain anchors nesprin-4 in the outer nuclear membrane in a SUN-dependent manner, with its kinesin-binding N-terminal region in the cytoplasm; nesprin-4 localizes to the nuclear envelope of hair cells and truncating DFNB76 mutants lose this localization. Supporting Evidence: PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. PMID:23348741 SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. file:human/SYNE4/SYNE4-uniprot.txt Localization at the nucleus outer membrane requires the presence of SUN1. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro KASH domain (IPR012315) to membrane mapping. Reason: Correct but general; nesprin-4 is a tail-anchored (type IV) membrane protein of the outer nuclear membrane. Supporting Evidence: file:human/SYNE4/SYNE4-uniprot.txt Nucleus outer membrane PMID:23348741 SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic inference that nesprin-4 is part of the SUN-KASH nuclear membrane tethering complex. Reason: Nesprin-4 forms LINC complexes with SUN1 (and SUN2) that couple kinesin-1 and microtubules to the nucleus, but its roles are somatic (hair cells, secretory epithelia); there is no evidence of a meiotic function (the meiotic KASH protein is KASH5). GO:0034993 is the meiosis-specific child; consistent with the SUN1, SUN2, SYNE1 and SYNE2 reviews, the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is appropriate, and fits nesprin-4 particularly well as a microtubule-motor-coupled KASH protein. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN002728347 SUPPORTS SOURCE BUT NOT TARGET Nesprin-4 PAINT node. Membership of the SUN-KASH tethering complex is inherited correctly, but the meiosis-specific child does not fit nesprin-4, whose known functions are somatic. UniProtKB:Q8N205 SUPPORTS TRANSFER Nesprin-4's own IPI (SUN2-KASH4 crystal structure, PMID:33058875) grounds complex membership; the evidence supports the non-meiotic parent GO:0106094. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:33393904 A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. PMID:23348741 These results demonstrate that nesprin-4 and Sun1 play an essential role in the basal positioning of OHC nuclei and at the same time are essential for the maintenance of OHC viability. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IEA GO_REF:0000002 | MODIFY | Summary: InterPro SYNE4 family (IPR030268) mapping to the meiotic LINC complex. Reason: Nesprin-4 forms LINC complexes with SUN1 (and SUN2) that couple kinesin-1 and microtubules to the nucleus, but its roles are somatic (hair cells, secretory epithelia); there is no evidence of a meiotic function (the meiotic KASH protein is KASH5). GO:0034993 is the meiosis-specific child; consistent with the SUN1, SUN2, SYNE1 and SYNE2 reviews, the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is appropriate, and fits nesprin-4 particularly well as a microtubule-motor-coupled KASH protein. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: file:human/SYNE4/SYNE4-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. PMID:23348741 These results demonstrate that nesprin-4 and Sun1 play an essential role in the basal positioning of OHC nuclei and at the same time are essential for the maintenance of OHC viability. |
| GO:0034993 meiotic nuclear membrane microtubule tethering complex | IPI PMID:33058875 Structural Analysis of Different LINC Complexes Reveals Dist... | MODIFY | Summary: Crystal structure of SUN2 bound to the nesprin-4 KASH peptide. Reason: Nesprin-4 forms LINC complexes with SUN1 (and SUN2) that couple kinesin-1 and microtubules to the nucleus, but its roles are somatic (hair cells, secretory epithelia); there is no evidence of a meiotic function (the meiotic KASH protein is KASH5). GO:0034993 is the meiosis-specific child; consistent with the SUN1, SUN2, SYNE1 and SYNE2 reviews, the non-meiotic parent GO:0106094 nuclear membrane microtubule tethering complex is appropriate, and fits nesprin-4 particularly well as a microtubule-motor-coupled KASH protein. Proposed replacements: nuclear membrane microtubule tethering complex Supporting Evidence: PMID:33058875 We solved high-resolution crystal structures of SUN2522-717 in complex with KASH3948-975, KASH4377-404, and KASH5542-562, which complement our previously published SUN2-KASH1 and SUN2-KASH2 complexes. PMID:23348741 These results demonstrate that nesprin-4 and Sun1 play an essential role in the basal positioning of OHC nuclei and at the same time are essential for the maintenance of OHC viability. |
| GO:0045198 establishment of epithelial cell apical/basal polarity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference (PAINT node seeded by mouse Syne4) of a role in establishing epithelial apical/basal polarity. Reason: The mouse source annotation derives from Roux et al. (2009), in which nesprin-4 expression relocated the centrosome and Golgi relative to the nucleus through kinesin-1 binding, suggesting a contribution to secretory epithelial organization; the full text is not available here, so the curator's judgement is respected. However, the more specific and better-supported role is kinesin-dependent positioning of the nucleus: in Nesp4 knockout mice outer hair cells form and polarize normally but fail to keep their nuclei basal. Nesprin-4 therefore contributes to one aspect of apicobasal cell organization (nuclear position) rather than establishing polarity per se; kept as non-core. Supporting Evidence: PMID:19164528 Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. file:human/SYNE4/SYNE4-uniprot.txt Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity). PMID:23348741 In both Nesp4-/- and Sun1-/- mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. PMID:23348741 In both mutants, the nuclei in OHCs, the auditory cells most affected by the loss of these 2 LINC complex proteins, showed a dramatic repositioning from a basal to apical location. |
| GO:0045198 establishment of epithelial cell apical/basal polarity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Syne4. Reason: The mouse source annotation derives from Roux et al. (2009), in which nesprin-4 expression relocated the centrosome and Golgi relative to the nucleus through kinesin-1 binding, suggesting a contribution to secretory epithelial organization; the full text is not available here, so the curator's judgement is respected. However, the more specific and better-supported role is kinesin-dependent positioning of the nucleus: in Nesp4 knockout mice outer hair cells form and polarize normally but fail to keep their nuclei basal. Nesprin-4 therefore contributes to one aspect of apicobasal cell organization (nuclear position) rather than establishing polarity per se; kept as non-core. Supporting Evidence: PMID:19164528 Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. file:human/SYNE4/SYNE4-uniprot.txt Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity). PMID:23348741 In both Nesp4-/- and Sun1-/- mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. PMID:23348741 In both mutants, the nuclei in OHCs, the auditory cells most affected by the loss of these 2 LINC complex proteins, showed a dramatic repositioning from a basal to apical location. |
| GO:0045198 establishment of epithelial cell apical/basal polarity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse nesprin-4 (Roux et al. 2009). Reason: The mouse source annotation derives from Roux et al. (2009), in which nesprin-4 expression relocated the centrosome and Golgi relative to the nucleus through kinesin-1 binding, suggesting a contribution to secretory epithelial organization; the full text is not available here, so the curator's judgement is respected. However, the more specific and better-supported role is kinesin-dependent positioning of the nucleus: in Nesp4 knockout mice outer hair cells form and polarize normally but fail to keep their nuclei basal. Nesprin-4 therefore contributes to one aspect of apicobasal cell organization (nuclear position) rather than establishing polarity per se; kept as non-core. Supporting Evidence: PMID:19164528 Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. file:human/SYNE4/SYNE4-uniprot.txt Hence may contribute to the establishment of secretory epithelial morphology by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity). PMID:23348741 In both Nesp4-/- and Sun1-/- mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. PMID:23348741 In both mutants, the nuclei in OHCs, the auditory cells most affected by the loss of these 2 LINC complex proteins, showed a dramatic repositioning from a basal to apical location. |
| GO:0140444 cytoskeleton-nuclear membrane anchor activity | ISS PMID:19164528 Nesprin 4 is an outer nuclear membrane protein that can indu... | NEW | Summary: Nesprin-4 binds kinesin-1 through its cytoplasmic region and SUN1/SUN2 through its luminal KASH peptide, providing a kinesin-1 attachment site on the nuclear envelope. Reason: GOA carries no molecular function for nesprin-4 other than protein binding. The other KASH nesprins (SYNE1, SYNE2, SYNE3) and the SUN partners carry GO:0140444 for the same bridging role, so this is the same-role comparator and not a process gap. Evidence: kinesin-1 binding via a LEWD motif (abolished by LEWD-to-LEAA mutation) and SUN-dependent outer nuclear membrane localization, and human SUN1/SUN2-KASH4 crystal structures. Supporting Evidence: PMID:19164528 Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. file:human/SYNE4/SYNE4-uniprot.txt Behaves as a kinesin cargo, providing a functional binding site for kinesin-1 at the nuclear envelope. PMID:36211453 Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. PMID:36211453 this mutation prevents the interaction of Nesprin-4 and Kif5b PMID:33393904 A common SUN-KASH topology is achieved through structurally diverse 6:6 interaction mechanisms by distinct KASH proteins, including zinc-coordination by Nesprin-4. PMID:33058875 We solved high-resolution crystal structures of SUN2522-717 in complex with KASH3948-975, KASH4377-404, and KASH5542-562, which complement our previously published SUN2-KASH1 and SUN2-KASH2 complexes. |
| GO:0051647 nucleus localization | ISS PMID:23348741 The LINC complex is essential for hearing. | NEW | Summary: Nesprin-4, with SUN1, is required to keep outer hair cell nuclei at the base of the cell; loss of either causes apical nuclear displacement followed by hair cell degeneration and hearing loss. Reason: Participation test: nesprin-4 does part of the work by physically linking the nucleus to kinesin-1 and the microtubule cytoskeleton (it is the cargo attachment site on the nucleus, as a cargo adaptor is for vesicle transport), not merely being required; in vivo, AAV-delivered nesprin-4 carrying a mutated kinesin-binding LEWD motif fails to restore basal nuclear position, whereas wild-type nesprin-4 rescues it, showing that the nesprin-4 activity itself drives the step. Comparator: the other KASH nesprins that couple motors to the nucleus (SYNE1, SYNE2) carry nuclear migration terms. The broader term nucleus localization is chosen because the OHC phenotype is failure to maintain nuclear position rather than migration per se. Evidence is from mouse knockouts and the human orthologue is associated with the same hearing phenotype (DFNB76). Supporting Evidence: PMID:23348741 These results demonstrate that nesprin-4 and Sun1 play an essential role in the basal positioning of OHC nuclei and at the same time are essential for the maintenance of OHC viability. PMID:23348741 In both mutants, the nuclei in OHCs, the auditory cells most affected by the loss of these 2 LINC complex proteins, showed a dramatic repositioning from a basal to apical location. PMID:23348741 Therefore, we would predict that loss of nesprin-4, and hence kinesin-1, from the cytoplasmic face of the NE, should result in an untethering of the nucleus from the microtubule cytoskeleton and a subsequent inability to efficiently localize the nucleus to the base of the cell, which is precisely what we observed. PMID:36211453 Using in vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. PMID:36211453 Thus, the LEWD interaction domain in Nesprin-4 is required for proper nuclear positioning, hearing function, and survival of OHC. PMID:33350593 Syne4-/- mice have severe-to-profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. file:human/SYNE4/SYNE4-deep-research-falcon.md In Syne4-null OHCs, nuclei progressively move toward the apical region, followed by OHC degeneration and hearing loss. |
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Download this section (compressed HTML)Q: Does nesprin-4 bind kinesin light chains through W-acidic (LEWD-like) motifs as nesprin-2 does, and which kinesin light chain isoforms (KLC1 vs KLC4) are relevant in cochlear hair cells?
Suggested experts: kinesin biologists, nuclear envelope biologists
Q: Is outer hair cell degeneration in SYNE4 deficiency a direct consequence of mispositioned nuclei (e.g. altered electromotility or mechanical stress), and should sensory perception of sound be annotated to nesprin-4 or regarded as a downstream phenotype?
Suggested experts: auditory neuroscientists, GO editors
Q: What is the functional significance of zinc coordination by the KASH4 CCSH motif in SUN1-nesprin-4 6:6 assemblies in vivo?
Suggested experts: structural biologists
Experiment: Rescue Syne4 knockout outer hair cells (or cultured epithelial cells) with nesprin-4 lacking the kinesin-binding region or carrying CCSH-to-SSSS KASH mutations, and assay basal nuclear position and hair cell survival.
Hypothesis: Both kinesin-1 binding and stable SUN1-KASH4 assembly are required for nesprin-4 to anchor outer hair cell nuclei basally and maintain hair cell viability.
Type: genetic rescue and imaging
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