PROSITE documentation PDOC52096

Scaffold anchor of CK1 (SACK1) domain profile

Members of the casein kinase 1 (CK1) family of serine-threonine protein kinases are implicated in the regulation of many cellular processes, including the cell cycle, circadian rhythms, and Wnt and Hedgehog signaling. Because these kinases exhibit constitutive activity in biochemical assays, it is likely that their activity in cells is controlled by subcellular localization, interactions with inhibitory proteins, targeted degradation, or combinations of these mechanisms. CK1 enzymes in vertebrates include the α, α-like, delta, apsilon, γ1, γ2, and γ3 isoforms, all of which are serine-threonine protein kinases. CK1 isoforms consist of a highly conserved N-terminal kinase domain that has little homology outside this family. FAM83 proteins, through their association with CK1 isoforms, could restrict the function of CK1 enzymes in cells by directly controlling their subcellular localization and perhaps their activity, stability, or substrate specificity. Different FAM83 proteins deliver CK1 isoforms to unique subcellular compartments. All eight members of the FAM83 family (FAM83A to FAM83H) are conserved in vertebrates and interact with the α and α-like isoforms of CK1; FAM83A, FAM83B, FAM83E, and FAM83H also interact with the delta and epsilon isoforms of CK1. The interaction of FAM83 proteins with CK1 isoforms is mediated by the N-terminal highly conservative scaffold anchor of CK1 (SACK1) domain of ~300 amino acids that characterizes the FAM83 family. The SACK1 domain of FAM83 proteins appears to associate directly with the kinase domain of CK1 isoforms and do so independently of CK1 catalytic activity [1,2,3].

The structure of the SACK1 domain, also known as the polypeptide anchor of CK1 (PACK1) domain, reveals a unique dimer with phospholipase D-like (PLD-like) fold (see <PDB: 4URJ>). However, the prototypic catalytic triad of PLD, which is characterized by the presence of an H-X-K-X-X-X-X-D (HKD) sequence motif (see <PDOC50035>), is not conserved in FAM83 proteins, and no PLD activity for any of the FAM83 proteins has been reported. Typically, two HKD motifs exist within each PLD protein, with the two HKD motifs coming together to form the catalytic core of the enzyme. FAM83 proteins, on the other hand, have only one HKD motif, and the histidine residue within the motif is absent from all but FAM83D (also known as CHICA). In the absence of catalytic activity, it is likely that the SACK1 domain has evolved to espouse novel function(s) in biology. The PLD-like fold is preceded by a region which folds into three α-helices (α1, α2 and α3) and is accordingly referred to as 3-helix region. A loop featuring a P-X-L-[DE]-L-G-W-P pattern, which is particularly well-preserved, separates them. It has been suggested that this loop, and the P-X-L-[DE]-L-G-W-P motif, play a relevant role in the protein structure and/or function [1.2.3].

The profile we developed covers the entire SACK1 domain.