Birds use the magnetic field of the Earth to navigate during their annual migratory travel. The possible mechanism to explain the biophysics of compass sense involves electron transfers within the photoreceptive protein cryptochrome; however, how the information about the magnetic field is passed on from cryptochrome to the rest of the cell and eventually to the bird's brain, is still unknown. In order for the signal of this magnetic compass to work, the signal needs to be passed on in a process called signal transduction. It remains to be shown which other proteins or molecules may interact with cryptochrome in order for this magnetic sense to work.
You can read more about the avian magnetic compass here.
The ISCA1 complex with Drosophila melanogaster cryptochrome
A study [Qin et al., 2016] claimed that the sensitivity to changes in the magnetic field is enhanced by coupling to an iron rich polymer complex which couples to multiple cryptochromes. For the iron sulphur clusters to participate in the compass sense, they either need to donate an electron to a specific tryptophane in the cryptochome or accept an electron from the flavin adenine dinucleotide (FAD) co-factor in the cryptochrome. To validate the claim, an independent reconstruction of such a complex and description of its interaction with Drosophila melanogaster cryptochromes is needed. The polymer complex consists of iron sulphur containing assembly ISCA1 protein monomers with internally bound iron sulphur clusters and simultaneously binds ten cryptochromes, shown in Fig. 1. Homology modelling and crystal packing structure of the used proteins are both used to construct the large cryptochrome-ISCA1 complex, which reveals that the iron sulphur clusters are too far away to participate in any electron transfer whatsoever.
The dynamic behaviour of the cryptochrome-ISCA1 complex is monitored to investigate both the time-evolution of the distance between the co-factors involved in electron transfer, and the interaction energy between cryptchrome and ISCA1, to see if the cryptochromes stick to ISCA1 and if they do so consistently along the rod. As seen in Fig. 2, the interaction energy is non-homologous along the ISCA1-rod, revealing that the complex likely does not exist in the proposed form. The large distance between the cofactors participating in electron factors rules out that this cryptochrome interaction has any relevance to magnetoreception. A more interesting interaction partner to cryptochrome is still sought after.
The ISCA1 complex with Erithacus rubecula cryptochrome
Since European robin and fruit fly cryptochromes are different, to test the hypothesis of ISCA1 complex in regards to the bird's migration, an investigation with the cryptochrome of European robin was undertaken.
The performed analysis aimed to consider 10 different possible spatial-binding modes between the ISCA1 complex and CRY4 (shown in Fig. 3) to reveal if any are favorable, as well as whether the intraprotein distances of these configurations would potentially permit any enhancements of the chemical magnetoreception mechanism in E. rubecula CRY4. The distances between the active sites of CRY (FAD and terminal tryptophan) and the nearest Fe2S2 clusters in the ISCA1-complex were measured for all the 10 configurations (shown in Table 4.) but turned out to be significantly larger than those expected for an efficient and realistic electron transfer.
In conclusion, although the findings of this study indicate that CRY4 and the ISCA1 complex can bind to each other, they do so very weakly due to the low number of found low-energy binding configurations, and the large distance between the radical pair in CRY and the Fe2S2 cluster in the ISCA1 complex eliminates the possibility of ISCA1 being involved in a joined electron transfer. This makes the ISCA1-CRY4 binding likely insignificant with respect to magnetoreception and ISCA1 an unlikely interaction partner for CRY4.
Can ascorbate play a role?
It was proposed in [Alpha A. Lee et al.; J. R. Soc. Interface, 11, 20131063 (2014)] that perhaps ascorbate, the ionic form of ascorbic acid (vitamin C), might be involved in magnetoreception, if this small molecule could get close enough to the surface-exposed tryptophan radical that is present in cryptochrome after photoactivation, and transfer an electron - leading to a radical pair between FAD and ascorbate instead. The central question in the ascorbate hypothesis is, therefore, whether the electron transfer from ascorbate to the tryptophan radical can happen.
Ascorbate was proposed to be involved in magnetoreception because its radical form has very small hyperfine interactions, i.e. very little coupling between the unpaired electronic spin and the spins of magnetic nuclei in ascorbate. Having small hyperfine interactions was shown to be desirable for one of the radicals in a radical pair, when paired with an FAD radical, since such a radical pair was shown to have a high sensitivity to the geomagnetic field - much more sensitive than an FAD/Tryptophan radical pair.
It was shown in [Nielsen et al.; J. R. Soc. Interface, 2017] using molecular dynamics simulations that ascorbate ions can indeed get close, and bind near the tryptophan radical as illustrated in Fig. 4. Furthermore the binding time of ascorbate was studied through a large set of additional simulations, and turned out to be about 1 ns as illustrated in Fig. 5.
At the same time it was shown, however, that the expected electron transfer from ascorbate to the tryptophan radical appears to be much too slow to have any impact, and it was therefore concluded that ascorbate is unlikely to play any role in magnetoreception unless exceptionally high ascorbate concentrations are found within the cryptochrome-containing cells.