MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
Biochem Soc Trans. 2018 Jun 19;46(3):761-771. doi: 10.1042/BST20160277. Epub 2018 Jun 5.
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.
FAM83（家族与序列相似性 83）家族的八成员是仅存在于脊椎动物中的蛋白质，其特征是 N 端存在保守的未知功能的 DUF1669 结构域。DUF1669 结构域包含一个保守的磷脂酶 D（PLD）样催化基序。然而，FAM83 蛋白不显示 PLD 催化（PLDc）活性，并且每个 FAM83 成员中存在的伪 PLDc 基序缺乏天然 PLDc 基序的关键元素。在没有催化活性的情况下，很可能 DUF1669 结构域已经进化出生物学中的新功能。最近的研究表明，DUF1669 结构域介导与丝氨酸/苏氨酸蛋白激酶 CK1（酪蛋白激酶 1）家族的不同同工型的相互作用。反过来，不同的 FAM83 蛋白，其在 DUF1669 结构域外具有独特的氨基酸序列，将 CK1 同工型递送到独特的亚细胞隔室。作为最早发现的蛋白激酶之一，CK1 同工型被认为是组成性激活的，并且已知控制着众多的生物学过程。然而，它们的激酶活性、底物选择性和亚细胞定位的调节仍然是一个谜。现在出现的证据支持 DUF1669 结构域和 FAM83 蛋白在 CK1 生物学调节中的核心作用。
