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• W1996252425 abstract "Progressive phosphorylation of circadian clock proteins is a hallmark of time-keeping. In this issue of Molecular Cell, Querfurth et al., 2011Querfurth C. Diernfellner A.C.R. Gin E. Malzahn E. Höfer T. Brunner M. Mol. Cell. 2011; 43 (this issue): 713-722Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar demonstrate that phosphorylation of Neurospora FRQ induces a conformational change, which can account for its temporally gated degradation. Progressive phosphorylation of circadian clock proteins is a hallmark of time-keeping. In this issue of Molecular Cell, Querfurth et al., 2011Querfurth C. Diernfellner A.C.R. Gin E. Malzahn E. Höfer T. Brunner M. Mol. Cell. 2011; 43 (this issue): 713-722Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar demonstrate that phosphorylation of Neurospora FRQ induces a conformational change, which can account for its temporally gated degradation. Molecular circadian clocks enable organisms to adapt their physiology and behavior to daily variations in their environment. Eukaryotic clocks rely on negative feedback loops, namely the rhythmic synthesis of transcriptional repressors, which then subsequently rhythmically repress their own transcription. These transcription factors are also posttranslationally modified (for example, by phosphorylation, sumoylation, acetylation, and ubiquitination), and many reports have highlighted the importance of these events to circadian timing. Genetic studies in a number of organisms indicate that these modification events not only help set the pace of the clock to approximately 24 hr but are also necessary for the generation of circadian rhythms (Mehra et al., 2009Mehra A. Baker C.L. Loros J.J. Dunlap J.C. Trends Biochem. Sci. 2009; 34: 483-490Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Yet important aspects of these events and their regulation remain enigmatic. In the current issue of Molecular Cell, Querfurth et al., 2011Querfurth C. Diernfellner A.C.R. Gin E. Malzahn E. Höfer T. Brunner M. Mol. Cell. 2011; 43 (this issue): 713-722Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar provide substantial mechanistic detail by indicating a new role for phosphorylation: it regulates the timing of a conformational switch in the Neurospora circadian repressor protein FREQUENCY (FRQ), which leads to its degradation. Phosphorylation is the best-understood and perhaps the major posttranslational mechanism that modifies clock proteins. It is also an evolutionarily conserved phenomenon; clock proteins from bacteria to human display daily rhythms of phosphorylation. Importantly, several kinases that phosphorylate clock components function broadly in eukaryotes, such as the casein kinases Ck1 and Ck2. As some of these enzymes also function in plant clocks, it is highly likely that of these mechanisms were already functioning in the circadian clock of a common ancestor. The phosphorylation of circadian transcriptional repressors is particularly important. The synthesis of these proteins is under temporal control, and they are then progressively phosphorylated. These events appear to control the temporal regulation of repressor function, as they influence protein subcellular localization, dimerization, activity, and ultimately degradation (Mehra et al., 2009Mehra A. Baker C.L. Loros J.J. Dunlap J.C. Trends Biochem. Sci. 2009; 34: 483-490Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Several kinases are involved, and mutations in these enzymes lead to strong circadian phenotypes, including period lengthening, shortening, and even arrhythmicity (Mehra et al., 2009Mehra A. Baker C.L. Loros J.J. Dunlap J.C. Trends Biochem. Sci. 2009; 34: 483-490Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). One interpretation is that these phenotypes reflect misregulation of kinase activity, i.e., wild-type activity is temporally regulated, which contributes directly to period determination. Understanding the roles and the functions of individual phosphorylation sites on target clock proteins is critical, and numerous papers have mapped phosphorylation sites and correlated them with biological function. These efforts are exemplified by studies of the Ptacek and Fu groups. For example, a single amino acid change in the human circadian repressor PERIOD2 (hPER2) causes advanced sleep phase syndrome (FASPS). Affected individuals have a serine to glycine mutation within the casein kinase Iε binding region of the protein, which causes hypophosphorylation by CKIε (Toh et al., 2001Toh K.L. Jones C.R. He Y. Eide E.J. Hinz W.A. Virshup D.M. Ptácek L.J. Fu Y.H. Science. 2001; 291: 1040-1043Crossref PubMed Scopus (1093) Google Scholar). In addition, proper phosphorylation of serines in the N-terminal region of Drosophila PERIOD (dPER) (particularly serine 47) leads to the binding of the F box protein SLIMB and dPER degradation (Chiu et al., 2008Chiu J.C. Vanselow J.T. Kramer A. Edery I. Genes Dev. 2008; 22: 1758-1772Crossref PubMed Scopus (109) Google Scholar). More recently, phosphorylation of a small domain of dPER (called the Per-Short cluster) was shown to be responsible for the proper timing of dPER degradation (Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Intriguingly, this small domain includes serine 589 (Ser589), which is phosphorylated and is also the amino acid mutated in the original perS allele of Konopka and Benzer (Konopka and Benzer, 1971Konopka R.J. Benzer S. Proc. Natl. Acad. Sci. USA. 1971; 68: 2112-2116Crossref PubMed Scopus (1525) Google Scholar, Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar), which has a short circadian period of 19 hr. These examples lead to the notion that most phosphorylation sites control specific aspects of clock protein function with precise temporal roles. However, the recent mapping of phosphorylation sites with mass spectrometry has challenged this notion. Indeed, there are a large number of characterized phosphorylation sites in dPER (Chiu et al., 2008Chiu J.C. Vanselow J.T. Kramer A. Edery I. Genes Dev. 2008; 22: 1758-1772Crossref PubMed Scopus (109) Google Scholar). A staggering 113 sites were found within Neurospora FRQ (Baker et al., 2009Baker C.L. Kettenbach A.N. Loros J.J. Gerber S.A. Dunlap J.C. Mol. Cell. 2009; 34: 354-363Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, Tang et al., 2009Tang C.T. Li S. Long C. Cha J. Huang G. Li L. Chen S. Liu Y. Proc. Natl. Acad. Sci. USA. 2009; 106: 10722-10727Crossref PubMed Scopus (63) Google Scholar)! Is it possible that each subserves a specific role within the molecular clock? In the present issue of Molecular Cell, Querfurth and collaborators propose a more appealing explanation for many of these sites. They demonstrate that the progressive phosphorylation of FRQ by Ck1a leads to a buildup of charge in one region of the protein, which results in a conformational change and then FRQ degradation. Importantly, the change does not require a precise role for each phosphorylation event but is an aggregate property (Figure 1). The authors first show that many portions of FRQ are predicted to be unstructured but that two domains are organized into amphipathic α helices; they associate to create a CK1a-interaction domain, which then promotes the progressive phosphorylation of FRQ on many phosphorylation sites. Removal or mutation of the two domains abolishes the recruitment of CK1a and results in an unphosphorylated form of FRQ, which does not undergo degradation (Querfurth et al., 2011Querfurth C. Diernfellner A.C.R. Gin E. Malzahn E. Höfer T. Brunner M. Mol. Cell. 2011; 43 (this issue): 713-722Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Interestingly, PER also has a CK1 (doubletime) binding site (Kim et al., 2007Kim E.Y. Ko H.W. Yu W. Hardin P.E. Edery I. Mol. Cell. Biol. 2007; 27: 5014-5028Crossref PubMed Scopus (84) Google Scholar, Nawathean et al., 2007Nawathean P. Stoleru D. Rosbash M. Mol. Cell. Biol. 2007; 27: 5002-5013Crossref PubMed Scopus (51) Google Scholar), which is important for normal PER phosphorylation. By inspecting the isoelectric point of different FRQ regions, the authors note that charge distribution is heterogenous, with a basic N-terminal portion, and acidic middle and C-terminal portions. Using different biochemical and molecular tools, the authors show that the N-terminal portion associates with the C-terminal portion when unphosphorylated. Progressive phosphorylation of the many sites in the N-terminal portion decreases its isoelectric point and creates charge repulsion between the two regions, which ultimately leads to a conformational change of the protein. This was visualized by partial protease digestion, which shows that hypophosphorylated FRQ is less prone to proteolysis, i.e., more compact, whereas hyperphosphorylation enhances proteolysis. The inferred conformational change allows CK1a to access a previously hidden PEST sequence and leads to FRQ degradation (Figure 1). Remarkably, the described series of events—progressive phosphorylation, the structural change, and then degradation—extends to PER (Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). One curiosity is the phenotype of a failure to phosphorylate several serines within the Per-Short domain of dPER. This region contains Ser589, which is the site of the perS mutation, as mentioned above. It is normally phosphorylated (Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar), and all missense mutations of this amino acid (except for threonine—pleasingly) shorten circadian period (Rutila et al., 1992Rutila J.E. Edery I. Hall J.C. Rosbash M. J. Neurogenet. 1992; 8: 101-113Crossref PubMed Scopus (55) Google Scholar, Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Why does the failure to phosphorylate this serine and a few others in its vicinity lead to such dramatic, short period phenotypes? Do these specific phosphorylation events serve a precise timing role, which then delays the hyperphosphorylation program (Chiu et al., 2011Chiu J.C. Ko H.W. Edery I. Cell. 2011; 145: 357-370Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar)? An alternative possibility, inspired by the findings of Brunner and colleagues, is that mutations in this region just disrupt structure, a not unprecedented role for missense mutations. What is unusual is that short period per mutants are relative rare. Perhaps most missense mutations that disrupt structure fail to provide sufficient function for rhythmicity, i.e., they are arrhythmic or long period. This would be because their poor function gives rise to a failed clock or one that marches through the circadian program only weakly—and slowly. In this view, the unusual thing about the PERS mutant is its temporal effect: the PERS structure is predicted to be normal or nearly so throughout much of its daily program and then is disrupted earlier than WT PER to accelerate the structural transition that causes PER degradation. For PER and PERS as well as FRQ, it would be interesting to track structural transitions as a function of circadian time; for example, are they gradual or discrete, and when during the in vivo cycle do they occur? The study by Querfurth et al., 2011Querfurth C. Diernfellner A.C.R. Gin E. Malzahn E. Höfer T. Brunner M. Mol. Cell. 2011; 43 (this issue): 713-722Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar challenges the notion that each phosphorylation site has a precise role, controlling a specific aspect of protein function. In this new view, it is the number of phosphorylated residues, rather than the particular sites, that determines the transition kinetics between the closed and open conformations. This perspective could account for the poor conservation of overall PER sequence between species, i.e., what is important for much of the protein is not a precise sequence but local charge density and its change with time. In this context, it may be relevant that the perS region is not conserved in mammals. Still remaining, however, is a classic problem present in many different biological contexts. How does a continuous process result in a discrete event, i.e., how does a gradual increase in charge density result in a conformational change at a specific time? Are there as-yet-undiscovered feedback loops that contribute to this timing event? Understanding this problem will almost certainly require biochemical studies, where the slow, gradual phosphorylation events as well as the presumptive discrete structural transition can be reconstructed in vitro. Eukaryotic circadian clocks await this kind of biochemical breakthrough. Circadian Conformational Change of the Neurospora Clock Protein FREQUENCY Triggered by Clustered Hyperphosphorylation of a Basic DomainQuerfurth et al.Molecular CellSeptember 02, 2011In BriefIn the course of a day, the Neurospora clock protein FREQUENCY (FRQ) is progressively phosphorylated at up to 113 sites and eventually degraded. Phosphorylation and degradation are crucial for circadian time keeping, but it is not known how phosphorylation of a large number of sites correlates with circadian degradation of FRQ. We show that two amphipathic motifs in FRQ interact over a long distance, bringing the positively charged N-terminal portion in spatial proximity to the negatively charged middle and C-terminal portion of FRQ. Full-Text PDF Open Archive" @default.
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• W1996252425 title "A New Twist on Clock Protein Phosphorylation: A Conformational Change Leads to Protein Degradation" @default.
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