Research ArticleCell Biology

The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms

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Science Signaling  22 May 2018:
Vol. 11, Issue 531, eaao2341
DOI: 10.1126/scisignal.aao2341

Subcellular targeting of CK1

FAM83 proteins participate in various cellular processes and are characterized by an N-terminal “domain of unknown function” called DUF1669. Fulcher et al. found that FAM83 family members interacted with a specific subset of casein kinase 1 (CK1) isoforms in vitro through the DUF1669 domain. Each of the eight FAM83 family members exhibited a distinct pattern of subcellular localization and colocalized with specific CK1 isoforms in cultured cells. Experiments in which DUF1669 domains were swapped among FAM83 family members suggested that DUF1669 determines the specificity of the FAM83 protein for particular CK1 isoforms. Because CK1 isoforms are thought to be constitutively active protein kinases, the ability of FAM83 proteins to anchor CK1 isoforms may be an important mechanism for targeting CK1 activity to specific subcellular locations and substrates.


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. We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A to FAM83H) interacted with the α and α-like isoforms of CK1; FAM83A, FAM83B, FAM83E, and FAM83H also interacted with the δ and ε isoforms of CK1. We detected no interaction between any FAM83 member and the related CK1γ1, CK1γ2, and CK1γ3 isoforms. Each FAM83 protein exhibited a distinct pattern of subcellular distribution and colocalized with the CK1 isoform(s) to which it bound. The interaction of FAM83 proteins with CK1 isoforms was mediated by the conserved domain of unknown function 1669 (DUF1669) that characterizes the FAM83 family. Mutations in FAM83 proteins that prevented them from binding to CK1 interfered with the proper subcellular localization and cellular functions of both the FAM83 proteins and their CK1 binding partners. On the basis of its function, we propose that DUF1669 be renamed the polypeptide anchor of CK1 domain.

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