An Old Cofactor in a New Light: Adenosylcobalamin in Light‐Dependent Gene Regulation

Abstract

Adenosylcobalamin (AdoCbl, coenzyme B12) is one of Nature's most complex enzyme cofactors and enables difficult radical chemistry via cleavage of its covalent cobalt‐carbon bond. In a recently discovered bacterial pathway, however, AdoCbl is used in a completely new function: it is used as a light sensor in light‐dependent gene regulation. Here, AdoCbl binds to the transcription factor CarH to regulate expression of the carotenoid biosynthetic genes. Gene expression is only activated upon light exposure, leading to carotenoid production and protection of the cell from light‐induced damage. This elegant response mechanism to sunlight is found in hundreds of bacterial species.Here, we present the full structural characterization of the light‐sensing transcription factor CarH. In the dark, AdoCbl mediates formation of a CarH tetramer that positions the DNA‐binding domains on the DNA operator, blocking transcription. Exposure to light cleaves AdoCbl's Co‐C bond, triggering a conformational change that causes tetramer disassembly, dissociation from DNA, and transcription activation. Thus, CarH harnesses the light sensitivity of AdoCbl to drive a light‐dependent gene expression switch. These studies provide fundamental insight into a new mode of light‐dependent gene regulation and provide a new biological role for AdoCbl.This work is supported by the NIH (CLD), the Ministerio de Ciencia e Innovación–Spain (SP and ME‐A), and a MIT Poitras fellowship (MJ). CLD is a HHMI investigator.