The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock
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(2020) 18:182
COMMENTARY
Open Access
The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock Gian Carlo G. Parico1 and Carrie L. Partch1,2*
Abstract Cryptochrome (CRY) proteins play an essential role in regulating mammalian circadian rhythms. CRY is composed of a structured N-terminal domain known as the photolyase homology region (PHR), which is tethered to an intrinsically disordered C-terminal tail. The PHR domain is a critical hub for binding other circadian clock components such as CLOCK, BMAL1, PERIOD, or the ubiquitin ligases FBXL3 and FBXL21. While the isolated PHR domain is necessary and sufficient to generate circadian rhythms, removing or modifying the cryptochrome tails modulates the amplitude and/or periodicity of circadian rhythms, suggesting that they play important regulatory roles in the molecular circadian clock. In this commentary, we will discuss how recent studies of these intrinsically disordered tails are helping to establish a general and evolutionarily conserved model for CRY function, where the function of PHR domains is modulated by reversible interactions with their intrinsically disordered tails. Keywords: Cryptochrome, C-terminal tail, Circadian rhythms, Autoinhibition, Intrinsically disordered region, Intrinsically disordered protein
Background Across the kingdoms of life, the photolyase/cryptochrome family helps organisms respond or adapt to environmental stresses set in place as the sun rises and sets each day. DNA photolyases utilize a flavin adenine dinucleotide (FAD) co-factor to harvest blue light and catalyze the repair of UV-induced DNA lesions such as cyclobutane pyrimidine dimers or pyrimidine-pyrimidone (6–4) photoproducts [1, 2]. In contrast to their more ancient photolyase homologs, cryptochrome (CRY) proteins are defined by the loss of DNA repair activity, while they have gained other functions in cell signaling [3]. The N-terminal domain of CRY, known as the photolyase homology region (PHR), is structurally similar to photolyase; both are composed of an N-terminal α/β subdomain that forms a secondary pocket that binds an antenna chromophore such * Correspondence: [email protected] 1 Department of Chemistry and Biochemistry, UC Santa Cruz, Santa Cruz, USA 2 Center for Circadian Biology, UC San Diego, La Jolla, USA
as 5,10-methenyl-tetrahydrofolate (MTHF), and a Cterminal helical subdomain that contains the FADbinding pocket [4–6] (Fig. 1). Some CRY PHRs, such as those from mammals, do not co-purify with chromophores, while other CRY PHRs from plants, insects or vertebrates do [7–11]. Therefore, depending on co-factor binding, chromophore-binding CRYs have photoreceptive functions while others function independently of light. One way in which all cryptochromes differ structurally from photolyase is through the acquisition of a Cterminal intrinsically disordered region (IDR) known simply as the CRY tail (Fig. 1). In contrast to the highly conserved PHR domain, the tail is highly divergent between CRY paralogs and across differen
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