Cryptochrome 4

Cryptochrome 4

spinqualitylabelsall models Pigeon crypto chrome 4 complex with FAD, triethylene glycol, ethanediol, glycerol and PEG (PDB code 6pu0) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Description Cryptochrome 4 is believed to be a crucial protein involved in magentoreception, a function that allows birds to visualize magnetic fields. In most animals where it is present, it is located within both the outer segments of the double cones and long-wavelength cones in the eye . It is evolutionarily related to DNA Photolyase proteins, however is shows no DNA repair activity. It shows a weak circadian oscillation and has strong up regulation during migratory seasons (2.2x upregulated) . It binds FAD at physiological conditions; a necessary function for its photochemical function. It has “a construct truncated at the C terminus by 28 residues that contains the photolyase homology region (PHR) that demonstrates spectra consistent with bound FAD^ox in the ground state”. There is high efficiency of conversion of FAD^ox to FADH^rad as well as the conversions of FADH^rad to FADH^-, indicating that it is sensitive to low light intensity. Purpose This protein’s proposed function is visualization of magnetic fields though magnetoreception forming radical a pair upon photo-excitation for light-dependent magentoreception. The mechanism of magentoreception is based upon the CIDNP (chemically induced dynamic nuclear polarization) concept, the description of which is beyond the scope of this analysis. It shows a very weak circadian oscillation regulation, unlike other cryptochromes such as Cry1 which show a much stronger circadian oscillation. Composition & Function This protein's gene has 1,584 base pairs corresponding to 527 amino acid residues. It is made of a single chain and comprised mostly of alpha helices. The photosensitizer in this system that contributes to the CIDNP function for this protein is flavin adenine dinucleotide, FAD. Cryptochrome 4 contains a DNA photolyase homology domain, an FAD binding domain, and four tryptophan residues thought to be involved in radical-pair formation known as the Trp-tetrad. The residue Asn391 is adjacent to the N5 position of the FAD isoalloxazine ring which acts to promote the creation of a stable FADH^rad radicle. This function has been shown in cryptochrome 1 proteins which, normally having a Cys instead of a Asn residue at this point, have previously been mutated to have a Asn and exhibited an increase in quantum yield after this change. It is assumed that this function is present in Cryptochrome 4 and thus Asn 391 will lead to a selection of a stable FADH^rad state. Tyr319 is solvent exposed (a necessity for CIDNP function) and is located 3.9 angstrom away from Trp369 at the end of the Trp-tetrad. It is anchored in a solvent-filed cleft through a tightly bound water molecule bridging Tyr319 and Arg324 and Arg477. This Tyr319 is highly conserved in CRY4 proteins and shows significant importance in the outcome of quantum yields which will allow this protein to function at low intensities of light, a time which corresponds to the conditions under which many migratory birds may be traveling. It is currently believed that upon photo induction of the system, the trp-tetrad will transfer an electron to the bound FADH to produce FAD^rad and TrpH^rad+. The radical will then switch to Tyr319. There are 3 structural domains within cryptochrome 4 (N' blue to C' red), the first being the N-terminal alpha beta domain connected via a long flexible linker to the second domain, an all-helical C-terminal domain. This is then adjacent to the initial residues of a divergent C-terminal tail.This C-terminal tail is oriented toward the FAD-binding cleft where blue light excitation of this FAD-binding cleft can lead to conformational changes in the C-terminal tail. Adjacent to the adenine moiety of FAD is a conserved pocket that is occupied by a glycerol molecule. This pocket is an evolutionary remnant that, in proteolyses, contains residues necessary for DNA repair. Currently, this pocket is lined by trp290/trp397 and his353/his357 . The His353 will hydrogen bond with ribitol side chain of FAD. Importance Magentoreception is the ability of a bird to sense the Earth’s magnetic field and thus orient itself. Cryptochrome 4 is believed to be the instrumental protein that allows this function to take place in the bird. However, the exact mechanism of this function has not yet been definitively determined, though it is believed that the creation of a radical via photooxidation follows the proposed CIDNP function. Thus far, the functional data from the protein does not line up with the observed behavior of birds in that, birds can easily orient themselves in full daylight where as studies suggest that cryptochrome 4 will be most active in low light intensity environments such as dawn and dusk.

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Christian Kassebaum, Michal Harel, Alexander Berchansky