Switches.ELM

Switch #:

SWTI000670

Switch type:
Binary

Switch subtype:
Physicochemical compatibility

Description:
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.

Participants:
(1) S-phase kinase-associated protein 2 (SKP2)
(2) Importin subunit alpha-6 (KPNA5)

Interactions

Interaction #1 SKP2 - KPNA5

Interfaces
(1) TRG_NLS_MonoExtN_4 motif (₆₅PPRKRLKS₇₂) in S-phase kinase-associated protein 2 (SKP2)
(2) Armadillo/beta-catenin-like repeat_(112-450) in Importin subunit alpha-6 (KPNA5)

Interaction Regulation
PTM-dependent Inhibition (Acetylation of K₆₈ and K₇₁ on S-phase kinase-associated protein 2 (SKP2)) of the S-phase kinase-associated protein 2 (SKP2) TRG_NLS_MonoExtN_4 motif - Importin subunit alpha-6 (KPNA5) Armadillo/beta-catenin-like repeat interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: K₆₈: Histone acetyltransferase p300 (EP300)

Context

References

(1) Acetylation-dependent regulation of Skp2 function.
Inuzuka et al. Cell (2012)