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| Domain hiding | Altered binding specificity | Motif hiding | Composite binding site formation |
| Uncategorised | Rheostatic | Allostery | Avidity-sensing |
| Physicochemical compatibility | Pre-translational | Competition |
| Protein | Start | End | Switch Type | Switch Subtype | Switch Description | Information |
TRG_NLS - | |||||||
| PML_HUMAN | 476 | 490 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of Protein PML (PML), abrogating binding to Importin subunit alpha-1 (KPNA1) and import into the nucleus. | ||
| CDN1B_HUMAN | 152 | 166 | Specificity | Motif hiding | Phosphorylation of a 14-3-3-binding motif in the NLS of Cyclin-dependent kinase inhibitor 1B (CDKN1B) by RAC-alpha serine/threonine-protein kinase (AKT1) induces binding of 14-3-3 protein gamma (YWHAG), which hides the NLS and prevents binding to Importin subunit alpha-1 (KPNA1), thereby mediating cytoplasmic retention of Cyclin-dependent kinase inhibitor 1B (CDKN1B). Binding of 14-3-3 dimer involves an additional C-terminal 14-3-3-binding motif (see switch details). | ||
TRG_NLS_Bipartite_1 - Bipartite variant of the classical basically charged NLS. | |||||||
| PTHR_HUMAN | 124 | 144 | Binary | Physicochemical compatibility | Phosphorylation of T121 adjacent to the NLS of Parathyroid hormone-related protein (PTHLH) by Cyclin-dependent kinase 2 (CDK2) disrupts the interaction with Importin subunit beta-1 (KPNB1) and down-regulates nuclear import. | ||
| IMA1_YEAST | 44 | 58 | Specificity | Domain hiding | An intramolecular interaction between the importin beta-binding (IBB) domain and the NLS-binding pocket of Importin subunit alpha (SRP1) prevents binding of NLS cargo (e.g. Large T antigen) in the absence of Importin subunit beta-1 (KAP95) by hiding of the NLS-binding pocket. Binding of the IBB of Importin subunit alpha (SRP1) to Importin subunit beta-1 (KAP95) relieves this auto-inhibitory interaction and increases the affinity of Importin subunit alpha (SRP1) for NLS cargo. | ||
TRG_NLS_MonoCore_2 - Monopartite variant of the classical basically charged NLS. Strong core version. | |||||||
| KCC2D_RAT | 327 | 332 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of Isoform Delta 3 of Calcium/calmodulin-dependent protein kinase type II subunit delta (Camk2d), abrogating binding to Importin subunit alpha-1 (KPNA1) and nuclear import. This is due to an 11 amino acid insert encoded by exon 14. | ||
| FBXW7_HUMAN | 10 | 15 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of F-box/WD repeat-containing protein 7 (FBXW7), abrogating binding to Importin subunit alpha-1 (KPNA1). There are two other NLS motifs in the protein, meaning the isoform can still enter the nucleus. | ||
TRG_NLS_MonoExtC_3 - Monopartite variant of the classical basically charged NLS. C-extended version. | |||||||
| MDM2_HUMAN | 181 | 187 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of E3 ubiquitin-protein ligase Mdm2 (MDM2), abrogating binding to Importin subunit alpha-1 (KPNA1). The exclusion from the nucleus is not complete however, as another NLS (466-473) is speculated to target splice variants to the nucleus, however, to the annotator it seems more likely that splice variants can dimerise with full-length MDM2 and be simultaneously transported into nucleus. | ||
TRG_NLS_MonoExtN_4 - Monopartite variant of the classical basically charged NLS. N-extended version. | |||||||
| SWI6_YEAST | 161 | 167 | Binary | Physicochemical compatibility | Phosphorylation of S160 adjacent to the NLS of Regulatory protein SWI6 (SWI6) decreases nuclear import of this protein by decreasing the affinity for Importin subunit alpha (SRP1). | ||
| NFAC1_HUMAN | 262 | 269 | Binary | Physicochemical compatibility | Phosphorylation of S241 and S290 adjacent to the NLS of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) by Glycogen synthase kinase-3 beta (GSK3B) and Glycogen synthase kinase-3 beta (GSK3B) inhibits nuclear import of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) by disrupting its interaction with Importin subunit alpha-2 (KPNA2). Calcium-dependent dephosphorylation by calcineurin promotes nuclear import. | ||
| LT_SV40 | 126 | 132 | Specificity | Motif hiding | Inhibition of nuclear import of Large T antigen by phosphorylation-dependent (T124) binding of BRCA1-associated protein (BRAP). | ||
| VPAP_HCMVA | 425 | 432 | Specificity | Motif hiding | Inhibition of nuclear import of DNA polymerase processivity factor (UL44) by phosphorylation-dependent (T427) binding of BRCA1-associated protein (BRAP). | ||
| MKL1_MOUSE | 62 95 | 67 101 | Specificity | Motif hiding | Hiding of the NLS of MKL/myocardin-like protein 1 (Mkl1) by binding of G-actin to the RPEL motifs of MKL/myocardin-like protein 1 (Mkl1) prevents translocation of this transcription factor to the nucleus. | ||
| LT_SV40 | 126 | 132 | Specificity | Domain hiding | An intramolecular interaction between the importin beta-binding (IBB) domain and the NLS-binding pocket of Importin subunit alpha (SRP1) prevents binding of NLS cargo (e.g. Large T antigen) in the absence of Importin subunit beta-1 (KAP95) by hiding of the NLS-binding pocket. Binding of the IBB of Importin subunit alpha (SRP1) to Importin subunit beta-1 (KAP95) relieves this auto-inhibitory interaction and increases the affinity of Importin subunit alpha (SRP1) for NLS cargo. | ||
| UNG_HUMAN | 15 | 21 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of Uracil-DNA glycosylase (UNG), abrogating binding to Importin subunit alpha-1 (KPNA1) and import into the nucleus. In Isoform UNG1 of Uracil-DNA glycosylase (UNG) the NLS present in Isoform UNG2 of Uracil-DNA glycosylase (UNG) is replaced with a mitochondrial localisation signal (MLS), promoting different localisations of the different protein isoforms. | ||
| OGG1_HUMAN | 332 | 339 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) motif of N-glycosylase/DNA lyase (OGG1), abrogating binding to Importin subunit alpha-1 (KPNA1) and import into the nucleus. OGG1-1a (also known as Isoform Alpha of N-glycosylase/DNA lyase (OGG1)) has a C-terminal NLS motif that is absent in OGG1-2a (also known as Isoform Beta of N-glycosylase/DNA lyase (OGG1)) . Both have a weak mitochondrial localisation signal (MLS) in the N-terminal. | ||
| BRCA1_HUMAN | 501 | 508 | Binary | Pre‑translational | Alternative splicing removes the nuclear localisation signal (NLS) of Breast cancer type 1 susceptibility protein (BRCA1), abrogating binding to Importin subunit alpha-1 (KPNA1) and import into the nucleus. The study compared the full-length Brca1 splice variant (Isoform 1 of Breast cancer type 1 susceptibility protein (BRCA1)) to the Delta11b isoform (Isoform Delta11b of Breast cancer type 1 susceptibility protein (BRCA1)). The shorter isoform is missing exon 11b and differs in a number of ways. Firstly, it lacks an NLS and therefore has a cytoplasmic localisation. Also, when over-expressed, the Delta11b isoform was not toxic, suggesting nuclear localisation is important for Brca1's toxic behaviour. | ||
| SKP2_HUMAN | 65 | 72 | Binary | Physicochemical compatibility | Acetylation of S-phase kinase-associated protein 2 (SKP2) in its NLS inhibits binding to the Importin subunit alpha-6 (KPNA5). p300 acetylates SKP2 at K68 and K71 within SKP2's nuclear localisation signal, this stabilises SKP2 from Fizzy-related protein homolog (FZR1)-mediated degradation and facilitates its translocation into the cytoplasm. This process can be reversed by NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) that specifically deacetylates SKP2 facilitating its translocation back into the nucleus. In the cytosol, SKP2 acts to promote Cadherin-1 (CDH1) degradation in a Casein Kinase I dependent manner to promote cell migration. Casein kinase I recognises the MOD_CK1_1 motif in CDH1 phosphorylating at residues Ser840 and Ser842. | ||
| SKP2_HUMAN | 65 | 72 | Binary | Physicochemical compatibility | Acetylation of S-phase kinase-associated protein 2 (SKP2) in its NLS inhibits binding to the Importin subunit alpha-7 (KPNA6). p300 acetylates SKP2 at K68 and K71 within SKP2's nuclear localisation signal, this stabilises SKP2 from Fizzy-related protein homolog (FZR1)-mediated degradation and facilitates its translocation into the cytoplasm. This process can be reversed by NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) that specifically deacetylates SKP2 facilitating its translocation back into the nucleus. In the cytosol, SKP2 acts to promote Cadherin-1 (CDH1) degradation in a Casein Kinase I dependent manner to promote cell migration. Casein kinase I recognises the MOD_CK1_1 motif in CDH1 phosphorylating at residues Ser840 and Ser842. | ||