Cryptochrome and Magnetic Sensing
Animal Magnetoreception
Magnetic sensing, perhaps because it is a type of sensory perception inaccessible to humans, has long captivated the human imagination. Over the past 50 years, scientific studies have shown that a wide variety of living organisms have the ability to perceive magnetic fields and can use information from the earth's magnetic field in orientation behavior. Examples abound: salmon (Oncorhynchus nerka), sea turtles (Dermochelys coriacea), spotted newts (Notophthalmus viridescens), lobsters (Panulirus argus), honeybees (Apis mellifera), and fruitflies (Drosophila melongaster) can all perceive and utilize geomagnetic field information. But perhaps the most well-studied example of animal magnetoreception is the case of migratory birds (e.g. European robins (Erithacus rubecula), silvereyes (Zosterops l. lateralis), garden warblers (Sylvia borin)), who use the earth's magnetic field, as well as a variety of other environmental cues, to find their way during migration.
Fig. 1. The magnetic compass of the European robin (Erithacus rubecula) has been extensively studied by Wiltschko et al. and others. Magnetic field effects in plants (Arabidopsis thaliana) have also been observed. A radical pair mechanism within the protein cryptochrome may underlie both phenomena. (Images taken from here and here.)
The avian magnetic compass is a complex entity with many surprising properties. The basis for the magnetic sense is located in the eye of the bird, and furthermore, it is light-dependent, i.e., a bird can only sense the magnetic field if certain wavelengths of light are available. Specifically, many studies have shown that birds can only orient if blue light is present (although a recent study showed that they may orient in red light given sufficient accomodation time). The avian compass is also an inclination-only compass, meaning that it can sense changes in the inclination of magnetic field lines but is not sensitive to the polarity of the field lines. Under normal conditions, birds are sensitive to only a narrow band of magnetic field strengths around the geomagnetic field strength, but can orient at higher or lower magnetic field strengths given accomodation time.
A Radical-Pair-Based Avian Compass
Despite decades of study, the physical basis of the avian magnetic sense remains elusive. The two main models for avian magnetoreception are a magnetite-based model and a radical-pair-based model. The former suggests that the compass has its foundation in small particles of magnetite located in the head of the bird. The latter idea is that the avian compass may be produced in a chemical reaction in the eye of the bird, involving the production of a radical pair. A radical pair, most generally, is a pair of molecules, each of which have an unpaired electron. If the radical pair is formed so that the spins on the two unpaired electrons in the system are correlated (i.e. they begin in a singlet or triplet state), and the reaction products are spin-dependent (i.e., there are distinct products for the cases where the radical pair system is in an overall singlet vs. triplet state), then there is an opportunity for an external magnetic field to affect the reaction by modulating the relative orientation of the electron spins.
How could a radical pair reaction lead to a magnetic compass sense? Suppose that the products of a radical pair reaction in the retina of a bird could in some way affect the sensitivity of light receptors in the eye, so that modulation of the reaction products by a magnetic field would lead to modulation of the bird's visual sense, producing brighter or darker regions in the bird's field of view. (The last supposition must be understood to be speculative; the particular way in which the radical pair mechanism interfaces with the bird's perception is not well understood.) When the bird moves its head, changing the angle between its head and the earth's magnetic field, the pattern of dark spots would move across its field of vision and it could use that pattern to orient itself with respect to the magnetic field. This idea is explored in detail by Ritz et al (see below). Interestingly, studies have shown that migratory birds exhibit a head-scanning behavior when using the magnetic field to orient that would be consistent with such a picture. Such a vision-based radical-pair-based model would explain several of the unique characteristics of the avian compass, e.g., that it is light-dependent, inclination-only, and linked with the eye of the bird. It is also consistent with experiments involving the effects of low-intensity radio frequency radiation on bird orientation, as suggested by Canfield et al. (see below).
Cryptochrome
The question remains as to where, physically, this radical pair reaction would take place. It has been suggested that the radical pair reaction linked to the avian compass arises in the protein cryptochrome. Cryptochrome is a signaling protein found in a wide variety of plants and animals, and is highly homologous to DNA photolyase. There is some evidence that retinal cryptochromes may be involved in the avian magnetic sense. Detailed analysis of cryptochrome as a transducer for the avian compass would require an atomic-resolution structure of the protein, and unfortunately, no structure of avian cryptochrome is currently available. However, the structure of cryptochrome from a plant (Arabidopsis thaliana) is available, and the cryptochromes of plants and birds are structurally very similar. Recent experiments by Ahmad et al. (Ahmad, Galland, Ritz, Wiltschko and Wiltschko. Magnetic intensity affects cryptochrome-dependent responses in Arabidopsis thaliana. Planta, in press. DOI 10.1007/s00425-006-0383-0.) have shown that Arabidopsis seedlings exhibit a magnetic field effect. Processes involved with cryptochrome signaling (such as hypocotyl growth inhibition) are enhanced under a magnetic field of 5 G (as compared with an Earth-strength 0.5 G magnetic field).
Fig. 2. A chain of three tryptophan residues, Trp400, Trp377 and Trp324 are involved in the photoreduction of the FAD cofactor. During the electron-transfer process, radical pairs are formed between FADH and each of the tryptophans. The formation of these radical pairs permits a magnetic field effect in cryptochrome.
Both photolyase and cryptochrome internally bind the chromophore flavin adenine dinucleotide (FAD). In photolyase, the protein is brought to its active state via a light-induced photoreduction pathway involving a chain of three tryptophans. Studies suggest that cryptochrome also is activated by a similar photoreduction pathway. The hypothesized photoreduction pathway in cryptochrome involves three tryptophans conserved from photolyase, numbered Trp324, Trp377 and Trp400 in the Arabidopsis cryptochrome structure. Trp324 is located near the periphery of the protein body, and Trp400 is proximal to the flavin cofactor with Trp377 located in between. Before light activation of cryptochrome, the flavin cofactor is present in its fully oxidized FAD state. FAD absorbs blue light photons, being promoted thereby to an excited state, FAD*. FAD* is then protonated, likely from a nearby aspartic acid, producing FADH+. Once the electronically excited flavin is in the FADH+ state, light-induced electron transfer is initiated. An electron first jumps from the nearby Trp400 into the hole left by the excited electron in FADH+, forming FADH + Trp400+. An electron then jumps from Trp377 to Trp400, forming FADH + Trp377+, and subsequently from Trp324 to Trp377, forming FADH + Trp324+. Finally Trp324+ becomes deprotonated to Trp324dep, i.e., forming FADH + Trp324dep, fixing the electron on the FADH cofactor. The protein cryptochrome is thought to be in its active (signaling) state when the flavin is in this FADH form. An external magnetic field can interact with each of the three radical pair states (FADH + Trp400+, FADH + Trp377+, FADH + Trp324+) formed during the photoreduction process.
Magnetic Field Effect in Cryptochrome
The idea behind the magnetic field effect is illustrated in Fig. 3. Cryptochrome is brought to its active (signaling) state via the photoreduction process described above. However, cryptochrome could revert to its non-active form if ever the unpaired electron on FADH back-transfers to one of the three tryptophans. This back-transfer process is spin-dependent, as it can only take place if the spins of the two unpaired electrons on FADH and the tryptophan are in an overall singlet (antiparallel) state, rather than a triplet (parallel) state. The spins of the unpaired electrons precess about the local magnetic field, which consists of contributions from the surrounding nuclei as well as from the external magnetic field. As each of the electron spins precess, they change their orientation with respect to one another. For example, if the spins begin in a singlet (antiparallel) state, their precession will bring them out of alignment, introducing some triplet contribution. In this way, the presence of the external magnetic field can influence the precession of the electron spins and thereby influence the amount of time the spins spend in their singlet state. This, in turn, influences the probability for electron back-transfer and therefore the amount of time that cryptochrome spends in its signaling state.
Fig. 3. Shown here is a semi-classical description of the magnetic field effect on the radical pairs between FADH and tryptophan in cryptochrome. The unpaired electron spins (S1 and S2) precess about a local magnetic field produced by the addition of the external magnetic field B with contributions I1 and I2 from the nuclear spins on the two radicals. The spin precession continuously alters the relative spin orientation, causing the singlet (anti-parallel) to triplet (parallel) interconversion which underlies the magnetic field effect. Electron back-transfer from a tryptophan to FADH quenches cryptochrome's active state. However, this back-transfer can only take place when the electron spins are in the singlet state, and this spin-dependence allows the external magnetic field, B, to affect cryptochrome activation.
Computational studies on a model of the photoreduction pathway in cryptochrome have shown that the magnetic field effect described above can have an effect on cryptochrome activation. The model used in our recent paper of the cryptochrome's photoreduction pathway (Solov'yov, Chandler, Schulten; see below) makes use of realistic electron transfer rate constants and hyperfine coupling constants. Calculations involving this model predict that the magnetic field effect could alter cryptochrome's activation yield (the amount of time it spends in its active state) by approximately 10% over the range from 0 to 5 G. This is of the same order of magnitude as the magnetic field effects observed by experimentalists in Arabidopsis thaliana. The calculations also predict an angular dependence which matches the observed inclination-only magnetic sense of birds. It was also found that the magnetic field effect is highly sensitive to the hyperfine coupling constants for each nucleus; unfortunately these hyperfine constants are not known for cryptochrome (the values used in the calculation were those for the highly-similar photolyase). Also, computational constraints limited the number of nuclei that could be included in the calcualtion. Future studies should make use of exact hyperfine coupling constants (if they become available) and include all nuclei. Calculations such as this strongly suggest that a radical-pair-based magnetic sense involving cryptochrome is feasible, and this is an important first step in explaining and understanding the magnetic sense of animals.
News Coverage
Light receptor may be key in how animals use Earth's magnetic field
TCB Publications
Magnetic field effects in Arabidopsis thaliana cryptochrome-1. Ilia A. Solov'yov, Danielle Chandler, and Klaus Schulten. Biophysical Journal, In press.
A model for photoreceptor-based magnetoreception in birds. Thorsten Ritz, Salih Adem, and Klaus Schulten. Biophysical Journal, 78:707-718, 2000.
A perturbation treatment of oscillating magnetic fields in the radical pair mechanism using the Liouville equation. J. M. Canfield, R. L. Belford, P. G. Debrunner, and K. Schulten. Chemical Physics, 195:59-69, 1995.
A perturbation theory treatment of oscillating magnetic fields in the radical pair mechanism. Jeff M. Canfield, R. Linn Belford, Peter G. Debrunner, and Klaus Schulten. Chemical Physics, 182:1-18, 1994.
Model for a physiological magnetic compass. Klaus Schulten and Andreas Windemuth. In G. Maret, N. Boccara, and J. Kiepenheuer, editors, Biophysical Effects of Steady Magnetic Fields, volume 11 of Proceedings in Physics, pp. 99-106. Springer, Berlin, 1986.
Magnetic field effects on radical pair processes in chemistry and biology. Klaus Schulten. In J. H. Bernhard, editor, Biological Effects of Static and Extremely Low Frequency Magnetic Fields, pp. 133-140. MMV Medizin Verlag, Munich, 1986.
Magnetic field effects in chemistry and biology. Klaus Schulten. In J. Treusch, editor, Festkörperprobleme, volume 22, pp. 61-83. Vieweg, Braunschweig, 1982.
A biomagnetic sensory mechanism based on magnetic field modulated coherent electron spin motion. Klaus Schulten, Charles E. Swenberg, and Albert Weller. Zeitschrift für Physikalische Chemie, NF111:1-5, 1978.
maintained by Danielle Chandler