SignatureFinder enables sequence mining to identify cobalamin-dependent photoreceptor proteins.

Photoreceptors control cellular processes in response to light. Most photoreceptors sense blue or red light, but the recent discovery of the cobalamin-dependent photoreceptor, CarH, has expanded the wavelength range of photoreception to other regions of the electromagnetic spectrum to include the green light region. Further identification of cobalamin-dependent green light-sensitive photoreceptors has been hampered owing to poor annotation of the light responsiveness of cobalamin-binding domains (CBDs) in public databases. Here we report a computational workflow, SignatureFinder, that uses a combination of sequence and structural analyses to identify new light-responsive CBD-containing proteins. The light response of exemplar proteins containing the proposed signature were confirmed experimentally. A structural analysis of these new photoreceptors, including the crystal structure of a new CBD domain, highlights how the signature elements interact with the cobalamin chromophore to sense light. Database mining of 128 000 CBD-containing sequences using the identified signature revealed more diverse CBD-containing photoreceptors, thereby expanding the family of green-light photoreceptors. A SignatureFinder web server is available (https://enzymeevolver.com) for wider applications, including the identification of signature sequences of other biological ligands of interest.