The FAM83 family of proteins: from pseudo-PLDs to anchors for CK1 isoforms

Abstract

The eight members of the FAM83 (FAMily with sequence similarity 83) family of poorly characterised proteins are only present in vertebrates and are defined by the presence of the conserved DUF1669 domain of unknown function at their N-termini. The DUF1669 domain consists of a conserved phospholipase D (PLD)-like catalytic motif. However, the FAM83 proteins display no PLD catalytic (PLDc) activity, and the pseudo-PLDc motif present in each FAM83 member lacks the crucial elements of the native PLDc motif. In the absence of catalytic activity, it is likely that the DUF1669 domain has evolved to espouse novel function(s) in biology. Recent studies have indicated that the DUF1669 domain mediates the interaction with different isoforms of the CK1 (casein kinase 1) family of Ser/Thr protein kinases. In turn, different FAM83 proteins, which exhibit unique amino acid sequences outside the DUF1669 domain, deliver CK1 isoforms to unique subcellular compartments. One of the first protein kinases to be discovered, the CK1 isoforms are thought to be constitutively active and are known to control a plethora of biological processes. Yet, their regulation of kinase activity, substrate selectivity and subcellular localisation has remained a mystery. The emerging evidence now supports a central role for the DUF1669 domain, and the FAM83 proteins, in the regulation of CK1 biology.

Keywords: CK1; FAM83; PLD; Wnt proteins; cancer; casein kinase.

Figure 1.. The FAM83 family of proteins.

Schematic representation of the eight members (A–H) of the FAM83 proteins indicating the N-terminal conserved domain of unknown function DUF1669. The C-terminus of each FAM83 member contains unique amino acid sequences that do not offer many functional clues. The positions of the amino acids relative to the DUF1669 domain are indicated for each member.

Figure 2.. FAM83 proteins each contain one pseudo-PLDc motif.

The ‘HKD’ motifs, which define the catalytic core of the PLD enzymes, from human PLD1 and PLD2 (which contain two HKD motifs) and PLD6 (which contains one motif) are aligned with those from the FAM83 members using the Clustal Omega and BoxShade server. The first histidine (H) residue as well as identical residues conserved in more than 50% of the sequences are boxed in black and similar residues are boxed in grey. The positions of the HKD residues within the motifs are indicated by asterisks. All FAM83 proteins, except FAM83D, lack the first histidine and are therefore termed pseudo-PLDs.

Figure 3.. Alignment of the region in FAM83 DUF1669 domain that contains CK1-interacting residues.

The indicated regions of the DUF1669 domains of the FAM83 proteins are aligned using the Clustal Omega and BoxShade server. Identical residues conserved in more than 50% of the sequences are boxed in black and similar residues are boxed in grey. The conserved Asp (D) and Phe (F) residues, which abolish CK1 interaction when individually mutated to Ala (A), are indicated. Interestingly, the same Asp (D) residue is part of the HKD motif in FAM83 proteins.

Figure 4.. CK1 isoforms control many cellular processes.

A schematic representation of the many biological processes that CK1 isoforms are known to regulate. How the activity of CK1 isoforms is regulated for them to influence so many cellular processes remains a mystery.

Figure 5.. The FAM83 proteins act to target CK1 isoforms to distinct subcellular compartments and, potentially, substrates.

(A) FAM83 proteins and different CK1 isoforms colocalise in distinct subcellular compartments. (B) It is hypothesised that the FAM83 proteins target different CK1 isoforms to distinct subcellular compartments and substrates in response to different signals. The DUF1669 domain of FAM83 proteins serves as a CK1-binding domain.