Martell, J.D. et al. Nat. Biotechnol. http://dx.doi.org/10.1038/nbt.3563 (2016).

The reconstitution of split proteins such as split GFP can be harnessed to detect protein–protein interactions; however, the resulting fluorescence is dim when the interaction occurs in the extracellular space, such as at synapses. Martell et al. developed split horseradish peroxidase (sHRP), a reporter that exhibits high sensitivity because of enzyme-mediated signal amplification. sHRP survives formaldehyde fixation, although it may be necessary to supply its cofactor heme when analyzing extracellular protein–protein interactions. Because sHRP, like its parent enzyme HRP, accepts a variety of substrates, its activity can be detected by different means, including electron microscopy and fluorescence microscopy. The researchers applied the sHRP tool to detect synapses in the mouse visual system.