The structural and functional roles of the flavin cofactor FAD in mammalian cryptochromes

The importance of circadian rhythms in human health and disease calls for a thorough understanding of the underlying molecular machinery, including its key components, the flavin adenine dinucleotide (FAD)-containing flavoproteins cryptochrome 1 and 2. Contrary to their Drosophila counterparts, mammalian cryptochromes are direct suppressors of circadian transcription and act independently of light. Light-independence poses the question regarding the role of the cofactor FAD in mammalian cryptochromes. The weak binding of the cofactor in vitro argues against its relevance and might be a functionless evolutionary remnant. From the other side, the FAD-binding pocket constitutes the part of mammalian cryptochromes directly related to their ubiquitylation by the ubiquitin ligase Fbxl3 and is the target for protein-stabilizing small molecules. Increased supplies of FAD stabilize cryptochromes in cell culture, and the depletion of the FAD precursor riboflavin with simultaneous knock-down of riboflavin kinase affects the expression of circadian genes in mice. This review presents the classical and more recent studies in the field, which help to comprehend the role of FAD for the stability and function of mammalian cryptochromes.

[1]  C. Helfrich-Förster,et al.  The Gain and Loss of Cryptochrome/Photolyase Family Members during Evolution , 2022, Genes.

[2]  A. Kramer,et al.  Foundations of circadian medicine , 2022, PLoS biology.

[3]  R. Vabulas,et al.  Dynamic association of flavin cofactors to regulate flavoprotein function , 2022, IUBMB life.

[4]  Nuri Ozturk.  Light‐dependent reactions of animal circadian photoreceptor cryptochrome , 2021, The FEBS journal.

[5]  T. Hirota,et al.  Structural differences in the FAD-binding pockets and lid loops of mammalian CRY1 and CRY2 for isoform-selective regulation , 2021, Proceedings of the National Academy of Sciences.

[6]  Jiali Gao,et al.  Activation mechanism of Drosophila cryptochrome through an allosteric switch , 2021, Science Advances.

[7]  R. Allada,et al.  Circadian Mechanisms in Medicine. , 2021, The New England journal of medicine.

[8]  P. Taylor,et al.  A Case Study of Eukaryogenesis: The Evolution of Photoreception by Photolyase/Cryptochrome Proteins , 2020, Journal of Molecular Evolution.

[9]  Timo Engelsdorf,et al.  The DASH-type Cryptochrome from the Fungus Mucor circinelloides Is a Canonical CPD-Photolyase , 2020, Current Biology.

[10]  T. Hirota,et al.  An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals. , 2020, Cell chemical biology.

[11]  T. Hirota,et al.  Isoform-selective regulation of mammalian cryptochromes , 2020, Nature Chemical Biology.

[12]  M. W. Young,et al.  Molecular mechanisms and physiological importance of circadian rhythms , 2019, Nature Reviews Molecular Cell Biology.

[13]  R. Henning,et al.  Photoactivation of Drosophila melanogaster cryptochrome through sequential conformational transitions , 2019, Science Advances.

[14]  Wouter D Hoff,et al.  Photoreceptors Take Charge: Emerging Principles for Light Sensing. , 2018, Annual review of biophysics.

[15]  Kimberly A. Reynolds,et al.  An evolutionary hotspot defines functional differences between CRYPTOCHROMES , 2018, Nature Communications.

[16]  Thomas Walz,et al.  Macromolecular Assemblies of the Mammalian Circadian Clock. , 2017, Molecular cell.

[17]  Ying-Hui Fu,et al.  FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice. , 2017, Cell reports.

[18]  N. Scrutton,et al.  Vertebrate Cryptochromes are Vestigial Flavoproteins , 2017, Scientific Reports.

[19]  Dina Schneidman-Duhovny,et al.  Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1 , 2017, Proceedings of the National Academy of Sciences.

[20]  Nuri Ozturk.  Phylogenetic and Functional Classification of the Photolyase/Cryptochrome Family , 2017, Photochemistry and photobiology.

[21]  M. W. Young,et al.  Changes in active site histidine hydrogen bonding trigger cryptochrome activation , 2016, Proceedings of the National Academy of Sciences.

[22]  Christopher R. Jones,et al.  A Cryptochrome 2 mutation yields advanced sleep phase in humans , 2016, eLife.

[23]  L. Corrochano,et al.  Fungal cryptochrome with DNA repair activity reveals an early stage in cryptochrome evolution , 2015, Proceedings of the National Academy of Sciences.

[24]  M. Barile,et al.  Remaining challenges in cellular flavin cofactor homeostasis and flavoprotein biogenesis , 2015, Front. Chem..

[25]  C. Neusüss,et al.  Quantification of riboflavin, flavin mononucleotide, and flavin adenine dinucleotide in mammalian model cells by CE with LED‐induced fluorescence detection , 2015, Electrophoresis.

[26]  A. Sancar,et al.  Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock , 2014, Genes & development.

[27]  Shannon N Nangle,et al.  Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex , 2014, eLife.

[28]  A. Kramer,et al.  Interaction of Circadian Clock Proteins CRY1 and PER2 Is Modulated by Zinc Binding and Disulfide Bond Formation , 2014, Cell.

[29]  Sooyoung Chung,et al.  Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. , 2014, ACS chemical biology.

[30]  A. Sancar,et al.  Mechanism of Photosignaling by Drosophila Cryptochrome , 2013, The Journal of Biological Chemistry.

[31]  Weiman Xing,et al.  Crystal structure of mammalian cryptochrome in complex with a small molecule competitor of its ubiquitin ligase , 2013, Cell Research.

[32]  G. M. Liuzzi,et al.  FAD Synthesis and Degradation in the Nucleus Create a Local Flavin Cofactor Pool* , 2013, The Journal of Biological Chemistry.

[33]  A. Kramer,et al.  Structures of Drosophila Cryptochrome and Mouse Cryptochrome1 Provide Insight into Circadian Function , 2013, Cell.

[34]  A. Yonezawa,et al.  Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. , 2013, Molecular aspects of medicine.

[35]  Y. Fukada,et al.  FBXL21 Regulates Oscillation of the Circadian Clock through Ubiquitination and Stabilization of Cryptochromes , 2013, Cell.

[36]  Xinran Liu,et al.  Competing E3 Ubiquitin Ligases Govern Circadian Periodicity by Degradation of CRY in Nucleus and Cytoplasm , 2013, Cell.

[37]  Michele Pagano,et al.  SCFFbxl3 Ubiquitin Ligase Targets Cryptochromes at Their Cofactor Pocket , 2013, Nature.

[38]  Peter C. St. John,et al.  Identification of Small Molecule Activators of Cryptochrome , 2012, Science.

[39]  E. Gianazza,et al.  Human FAD synthase (isoform 2): a component of the machinery that delivers FAD to apo‐flavoproteins , 2011, The FEBS journal.

[40]  K. Yagita,et al.  The Potorous CPD Photolyase Rescues a Cryptochrome-Deficient Mammalian Circadian Clock , 2011, PloS one.

[41]  T. Ritz,et al.  The cryptochromes: blue light photoreceptors in plants and animals. , 2011, Annual review of plant biology.

[42]  A. von Haeseler,et al.  Distribution and Phylogeny of Light-Oxygen-Voltage-Blue-Light-Signaling Proteins in the Three Kingdoms of Life , 2009, Journal of bacteriology.

[43]  J. Brüning,et al.  Riboflavin kinase couples TNF receptor 1 to NADPH oxidase , 2009, Nature.

[44]  R. Stanewsky,et al.  Light-Dependent Interactions between the Drosophila Circadian Clock Factors Cryptochrome, Jetlag, and Timeless , 2009, Current Biology.

[45]  Joseph S. Takahashi,et al.  Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression , 2007, Cell.

[46]  Michele Pagano,et al.  SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins , 2007, Science.

[47]  M. Pagano,et al.  The After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period , 2007, Science.

[48]  A. Sancar,et al.  Structure and function of animal cryptochromes. , 2007, Cold Spring Harbor symposia on quantitative biology.

[49]  A. Sancar,et al.  A cryptochrome/photolyase class of enzymes with single-stranded DNA-specific photolyase activity , 2006, Proceedings of the National Academy of Sciences.

[50]  A. Sehgal,et al.  JETLAG Resets the Drosophila Circadian Clock by Promoting Light-Induced Degradation of TIMELESS , 2006, Science.

[51]  A. Sancar,et al.  Direct observation of thymine dimer repair in DNA by photolyase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Todo,et al.  The cryptochromes , 2005, Genome Biology.

[53]  Timothy Cardozo,et al.  Systematic analysis and nomenclature of mammalian F-box proteins. , 2004, Genes & development.

[54]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[55]  L. Miraglia,et al.  A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock , 2004, Neuron.

[56]  F. Inagaki,et al.  Binding of FAD to Cytochrome b558 Is Facilitated during Activation of the Phagocyte NADPH Oxidase, Leading to Superoxide Production* , 2004, Journal of Biological Chemistry.

[57]  S. Peirson,et al.  Melanopsin retinal ganglion cells and the maintenance of circadian and pupillary responses to light in aged rodless/coneless (rd/rd cl) mice , 2003, The European journal of neuroscience.

[58]  K. Yau,et al.  Diminished Pupillary Light Reflex at High Irradiances in Melanopsin-Knockout Mice , 2003, Science.

[59]  Minoru Kanehisa,et al.  Identification of a new cryptochrome class. Structure, function, and evolution. , 2003, Molecular cell.

[60]  I. Edery,et al.  Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime , 2002, Nature.

[61]  François Rouyer,et al.  The F-box protein Slimb controls the levels of clock proteins Period and Timeless , 2002, Nature.

[62]  Mark Gomelsky,et al.  BLUF: a novel FAD-binding domain involved in sensory transduction in microorganisms. , 2002, Trends in biochemical sciences.

[63]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[64]  Yan Liu,et al.  The C Termini of Arabidopsis Cryptochromes Mediate a Constitutive Light Response , 2000, Cell.

[65]  A Yasui,et al.  Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. , 1999, Science.

[66]  C. Weitz,et al.  Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. , 1999, Science.

[67]  D. V. Leenen,et al.  Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms , 1999, Nature.

[68]  Stephen J. Elledge,et al.  SKP1 Connects Cell Cycle Regulators to the Ubiquitin Proteolysis Machinery through a Novel Motif, the F-Box , 1996, Cell.