Menu

Close

Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

Daniel R. Kattnig, Claus Nielsen, Ilia A. Solov'yov

Preprint posted on May 17, 2018 https://www.biorxiv.org/content/early/2018/05/17/324962

Birds use a magnetic compass for orientation during their amazing migratory journeys. This study highlights the involvement of candidate regions of the putative Cry4 receptor molecule in magnetoreception related signal transduction.

Selected by Miriam Liedvogel

Background

Birds are able to use the Earth’s magnetic field as reference cue for orientation during their amazing migratory journeys. From behavioural experiments we know what characteristics of the magnetic field the birds are using, but we still don’t understand how birds are sensing the magnetic field.

The magnetic compass in migratory birds has been shown to be light-dependent, and theoretical physicists have suggested the reaction could be based on a radical pair reaction, where the ratio of singlet and triplet transient states of a radical pair could be indicative for the orientation of that molecule within the magnetic field. Cryptochromes have been suggested as promising candidates as they are the only known photosensitve proteins in the vertebrate eye that have the potential to form radical pairs. In theory, cryptochromes (Cry) in the bird’s eye undergo a specific chemical reaction that is governed by the direction of the Earth’s magnetic field, and could provide a signal for orientation.

Cryptochromes come in different flavours and are members of a multigene family of blue light photoreceptors. In birds, four different cryptochromes have been identified (Cry1a and Cry1b that are different splicing variants, Cry2 and Cry4) – but which of them could potentially act as the magnetosensor? Cryptochrome 4 stands out as the most promising candidate and receives most attention in this skating exhibition, because it comes with specific features that distinguish it clearly from other family members.

Cry4 has been detected in the retina of several bird species and is particularly suited as (unlike the other mentioned family members) expression levels are constant throughout the day and independent of a circadian rhythm. Importantly, expression levels are higher during the migratory season compared to periods of the year when these birds do not engange in oriented long-distance flights, which clearly supports its role as putative magnetosensor. Cry4 shows high affinity to bind the photacitve flavin cofactor (FAD) and undergoes light-dependent structural changes in the C-terminal end, which are investigated focally here. The protein structure of this promising magnetoreceptor molecule remains to be solved, but a homology model for Cry4 from the European robin (ErCry4), an iconic and well described study species in the field of bird migration, has been established.

Key findings

Illustration of the secondary structure of ErCry4 with mobile sites indicated in red.

Here the authors use this homology model to simulate structural reorganisations that accompany the photoreduction of the flavin cofactor and are able to demonstrate that photo-activation of the hypothesized magnetoreceptor molecule induces large-scale conformational changes on very short timescales. Excitingly, these molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4. Specifically, the photoreduction leads to the release of the C-terminal region, accompanied by structural rearrangements close to the binding site for the photacitve flavin cofactor binding site.

The authors highlight strengths and shortcomings of different modelling approaches and graphical representations that are used to identify common motifs of these mobile sites. Using a graph-based approach to describe the conformational dynamics of the potential magnetoreceptor protein upon photoactivation, the authors are able to show that these rearrangements appear to expose potential phosphorylation sites that have the potential to be functionally coupled to photoactivation. Although based on simulation data only so far, this provides the exciting possibility that these phosphorylation sites could have a function in modulating/deactivating the photo-transduction cascade.

The authors speculate this could be realised in a manner similar to the deactivation of rhodopsin (another retinal photopigment), where photoexcitation triggers conformational changes that lead to phosphorylation and subsequent regulation of downstream transduction steps in the visual process.

Summary and future prospects This paper reveals the identification of residual sites in the hypothesized magnetoreceptor protein Cry4 of migratory robin that undergo conformational changes triggered by photoactivation. Specifically, the authors identify the most promising sites to be located at the C-terminal tail of the protein or motifs closely coupled to that region. Importantly, these results identify candidate regions that are potentially involved in signal transduction related to magnetoreception and pave the avenue for experimentally testing these major regulators in subsequent experiments, possibly by targeted molecular manipulation of the focal sites. These exciting findings clearly call for support by experimental evidence from analogous studies on the crystal structures once available.

 

What I like about this work Understanding how birds perceive the Earth’s magnetic field and use this information to orient during their fascinating long migratory journeys is one of the key unresolved mysteries in sensory biology. This study capitalises on the recently published homology model of the candidate receptor molecule Cry 4 from European robins to identify key regulatory candidate regions and predict their involvement in magnetic compass orientation related signal transduction. Understanding the phenomenon of magnetoreception undoubtably needs a cross-disciplinary and highly integrative approach. This study provides a perfect example how theoretical prediction provide the necessary avenue for experimentalists and behavioural biologists to join in and design the diagnostic tests to challenge these findings in analogous studies and/or with complementary approaches.

And one question to the authors – and yes, I am asking for gut feeling here The transient radical pair is the one that is the one that is affected by and thus the one translating magnetic information into an oriented behavior. Here the the focus is on a radical pair state that is photoinduced from the dark state protein with the fully oxidised FAD cofactor. What is your feeling here – do you think this is “it”, i.e.the hero radical pair that runs for magnetoreceptor, or is it the fully reduced and then putatively reoxidise Cry4?

Tags: animal orientation, bird migration, magnetoreceptor

Posted on: 4th June 2018 , updated on: 6th June 2018

Read preprint (No Ratings Yet)




  • Author's response

    Daniel R. Kattnig shared

    This is a delicate question as it capitalizes on a vigorously discussed but currently undecidable aspect of magnetoreception in cryptochromes. The two main competitors are undoubtedly: [FAD W+], for which magnetic field effects have been documented in vitro, and [FADH O2], which is often disguised as [FADH Z] in order to hide concerns implicated by O2‘s fast spin relaxation precluding magnetic sensitivity in weak magnetic fields. The strongest support in favor of the reoxidation hypothesis, [FADH O2], is provided by an interesting study by Wiltschko et al. using flickering light to demonstrate that the magnetosensitive process could occur in the dark [1]. While stipulated by these experiments, the [FADH O2]-hypothesis is not without inconsistencies: The spin relaxation in O2 is too fast, and, contrary to popular assumption, does not explain the Zeeman resonance effect postulated to interfere with the animals’ magnetoreceptor unless the radicals are too far apart to act as a magnetosensitive radical pair [2]. Furthermore, the sensitivity to low light suggest that the radical pair is generated in a photo-reduction process [3]. Concerning fast spin relaxation, we have recently suggested a way of how this issue could be alleviated by a more complicated reaction scheme involving three instead of two radicals [4]. However, while promising, this research into radical triads (instead of pairs) is still in its infancy. Yet, my gut feeling is that these processes could be vastly more sensitive sensors than any radical pair. In fact, in this scenario O2 and a radical derived from the (photo-)oxidation of a protein residue such as tyrosine or tryptophan could be simultaneously relevant. Thus, could both schools be right in the end? It is not utterly inconceivable.

    I expect that the resolution of the crystal structure of the avian cryptochromes, in particular Cry4, and the identification of interaction partners will eventually shed light on the question of the identity of the radical pair/triad. Furthermore, key experiments like that in [1] will have to be independently repeated and extended (e.g. by using radio frequency perturbation in various frequency bands). I expect that in vitro magnetosensitivity will be found for the photo-reduction process in Cry4 similar to that established for the cryptochrome of D. melanogaster. Any magnetic field effect on the re-oxidation is yet to be found, but is admittedly much harder to establish unequivocally. It is my feeling that this question will not be easy to resolve and we will have to resort to refined theoretical calculations and experiments to uncover the actual sensory process. As for the current work, we do not think that the [FAD W+] vs. [FADH O2] question is relevant as for DmCry similar activation patterns have been established for the photo-induced radical pairs and the chemical generated flavin semiquinone.

    In any case, I rest assured that we are far from a conclusive picture and I am looking forward to new discoveries and directions.

     

    1. Wiltschko, R.; Ahmad, M.; Nießner, C.; Gehring, D.; Wiltschko, W., Light-dependent magnetoreception in birds: The crucial step occurs in the dark. J. R. Soc., Interface 2016, 13 (118), 20151010.
    2. Hiscock, H. G.; Mouritsen, H.; Manolopoulos, D. E.; Hore, P. J., Disruption of magnetic compass orientation in migratory birds by radiofrequency electromagnetic fields. Biophys. J. 2017, 113, 1475-1484
    3. Vanderstraeten, J.; Gailly, P.; Malkemper, E. P., Low-Light Dependence of the Magnetic Field Effect on Cryptochromes: Possible Relevance to Plant Ecology. Frontiers in Plant Science 2018, 9.
    4. Kattnig, D. R., Radical-Pair-Based Magnetoreception Amplified by Radical Scavenging: Resilience to Spin Relaxation. J. Phys. Chem. B 2017, 121 (44), 10215-10227.

    Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the animal behavior and cognition category:

    In vivo glucose imaging in multiple model organisms with an engineered single-wavelength sensor

    Jacob P. Keller, Jonathan S. Marvin, Haluk Lacin, et al.



    Selected by Stephan Daetwyler

    1

    Active behaviour during early development shapes glucocorticoid reactivity

    Luis A. Castillo-Ramírez, Soojin Ryu, Rodrigo J. De Marco



    Selected by Kathleen Gilmour

    Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins

    Kelsey M. Tyssowski, Jesse M. Gray



    Selected by Zheng-Shan Chong

    Establishment of the mayfly Cloeon dipterum as a new model system to investigate insect evolution

    Isabel Almudi, Carlos Martin-Blanco, Isabel Maria Garcia-Fernandez, et al.



    Selected by Ivan Candido-Ferreira

    1

    Regulation of modulatory cell activity across olfactory structures in Drosophila melanogaster

    Xiaonan Zhang, Kaylynn Coates, Andrew Dacks, et al.



    Selected by Rudra Nayan Das

    1

    Elaborate pupils in skates may help camouflage the eye

    Sean Youn, Corey Okinaka, Lydia Mathger



    Selected by Carola Yovanovich

    Distributed correlates of visually-guided behavior across the mouse brain

    Nicholas Steinmetz, Peter Zatka-Haas, Matteo Carandini, et al.



    Selected by Craig Bertram

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    1

    Predation risk and resource abundance mediate foraging behaviour and intraspecific resource partitioning among consumers in dominance hierarchies

    Sean Naman, Rui Ueda, Takuya Sato



    Selected by Rasmus Ern

    Antlions are sensitive to subnanometer amplitude vibrations carried by sand substrates

    Vanessa Martinez, Elise Nowbahari, David Sillam-Dussès, et al.



    Selected by James Foster

    Optogenetic manipulation of medullary neurons in the locust optic lobe

    Hongxia Wang, Richard B. Dewell, Markus U. Ehrengruber, et al.



    Selected by Ana Patricia Ramos

    Phenotypic landscape of schizophrenia-associated genes defines candidates and their shared functions

    Summer B. Thyme, Lindsey M. Pieper, Eric H. Li, et al.



    Selected by Daniel Grimes

    Using a robotic fish to investigate individual differences in social responsiveness in the guppy

    David Bierbach, Tim Landgraf, Pawel Romanczuk, et al.



    Selected by Rasmus Ern

    Small differences in learning speed for different food qualities can drive efficient collective foraging in ant colonies

    Felix B Oberhauser, Alexandra Koch, Tomer J Czaczkes



    Selected by James Foster

    Individual- and population-level drivers of consistent foraging success across environments

    Lysanne Snijders, Ralf HJM Kurvers, Stefan Krause, et al.



    Selected by Rasmus Ern

    From Armament to Ornament: Performance Trade-Offs in the Sexual Weaponry of Neotropical Electric Fishes

    Kory M. Evans, Maxwell J. Bernt, Matthew A. Kolmann, et al.



    Selected by Cassandra Donatelli

    Also in the biophysics category:

    The autophagic membrane tether ATG2A transfers lipids between membranes

    Shintaro Maeda, Chinatsu Otomo, Takanori Otomo



    Selected by Sandra Malmgren Hill

    Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics

    Charlotte S. Sørensen, Magnus Kjaergaard



    Selected by Tessa Sinnige

    1

    Spreading of molecular mechanical perturbations on linear filaments

    Zsombor Balassy, Anne-Marie Lauzon, Lennart Hilbert



    Selected by Lars Hubatsch

    Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins

    Kelsey M. Tyssowski, Jesse M. Gray



    Selected by Zheng-Shan Chong

    HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly

    C. Favard, J. Chojnacki, P. Merida, et al.



    Selected by Amberley Stephens

    Microfluidic protein isolation and sample preparation for high resolution cryo-EM

    Claudio Schmidli, Stefan Albiez, Luca Rima, et al.



    Selected by David Wright

    ENDOSOMAL MEMBRANE TENSION CONTROLS ESCRT-III-DEPENDENT INTRA-LUMENAL VESICLE FORMATION

    Vincent Mercier, Jorge Larios, Guillaume Molinard, et al.



    Selected by Nicola Stevenson

    1

    Planar differential growth rates determine the position of folds in complex epithelia

    Melda Tozluoğlu, Maria Duda, Natalie J Kirkland, et al.

    AND

    Buckling of epithelium growing under spherical confinement

    Anastasiya Trushko, Ilaria Di Meglio, Aziza Merzouki, et al.



    Selected by Sundar Naganathan

    2

    Microtubules stabilize intercellular contractile force transmission during tissue folding



    Selected by Ivana Viktorinová

    Dynamic Aha1 Co-Chaperone Binding to Human Hsp90

    Javier Oroz, Laura J Blair, Markus Zweckstetter



    Selected by Reid Alderson

    1

    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.



    Selected by Robert Mahen

    1

    Central spindle microtubules are strongly coupled to chromosomes during both anaphase A and anaphase B

    Che-Hang Yu, Stefanie Redemann, Hai-Yin Wu, et al.



    Selected by Federico Pelisch

    1

    Mechanical Stretch Kills Transformed Cancer Cells

    Ajay Tijore, Mingxi Yao, Yu-Hsiu Wang, et al.



    Selected by Joseph Jose Thottacherry

    Super-resolution Molecular Map of Basal Foot Reveals Novel Cilium in Airway Multiciliated Cells

    Quynh Nguyen, Zhen Liu, Rashmi Nanjundappa, et al.



    Selected by Robert Mahen

    Force inference predicts local and tissue-scale stress patterns in epithelia

    Weiyuan Kong, Olivier Loison, Pruthvi Chavadimane Shivakumar, et al.



    Selected by Sundar Naganathan

    Single molecule localization microscopy with autonomous feedback loops for ultrahigh precision

    Simao Coelho, Jongho Baek, Matthew S Graus, et al.



    Selected by Lars Hubatsch
    Close