Moonlighting molecules

Just when you thought you knew what your protein did, it goes off and does something completely different (and unexpected). This is called moonlighting, and is yet another reason drug discovery is hard. You can never be sure that your target is doing only what you think it’s doing.

Today’s example is PACAP, a neuromodulator/neurotransmitter made by neurons. Who knew that PACAP can and does act as an antibiotic when the brain is infected. [ Proc. Natl. Acad. Sci. vol. 118 e1917623117 ’21 ] does (PNAS no longer pages its journals, as last year’s total was over 33,000 !).   PACAP is a member of the vasoactive intestinal polypeptide, secretin, glucagon family of neuropeptides (mammals have over 100 neuropeptides according to the paper).

PACAP stands for Pituitary Adenylate Cyclase Activating Polypeptide. It comes in two forms containing 27 or 38 amino acids, both cleaved from a 176 amino acid precursor. There are 3 receptors for PACAP, all G Protein Coupled Receptors (GPCRs). A zillion functions have been ascribed to it, setting the circadian clock, protecting granule cells of the cerebellum. Outside the nervous system it is produced by immune cells in response to inflammatory conditions and antigenic stimulation. It is one of the most conserved neuropeptides throughout the course of evolution. Now we probably know why.

Showing how hard protein chemistry really is, PACAP is structurally similar to cathelicidin LL-37 an antimicrobial peptide, despite having less than 5% amino acid sequences in common. PACAP is cationic. Different sides of the protein have different characteristics, with one side being highly positively charged, and the other being hydrophobic (e.g. the protein is amphipathic). This is typical of antimicrobial peptides, and perturbation of microbial membranes by inducing negative Gaussian curvature probably explains its antibacterial activity.

In mouse models of Staph Aureus or Candida infections, PACAP is induced ‘up to’ 50 fold in the brain (or spleen or kidney) where it kills the bugs. Yet another reason drug discovery is so hard. We are mucking about in a system we barely understand.

There are many other examples of moonlighting proteins. Probably the best known is cytochrome c which is is a heme protein localized in the compartment between the inner and outer mitochondrial membranes where it functions to transfer electrons between complex III and complex IV of the respiratory chain. Oxidation and reduction of the iron atom in the heme along with movement along the mitochondrial intermembrane space allows it to schlep electrons between complexes of the respiratory chain.

All well and good. But cytochrome c also can tell a cell to commit suicide (apoptosis) when mitochondria are sufficiently damaged that cytochrome c can escape the intermembrane space. Who’d a thunk it?

How many more players are there in the cell (whose function we think we know) that are sneaking around — doing more things in heaven and Earth, Horatio, than are dreamt of in your philosophy?

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