Evolution of Antimicrobial Peptides: A View from the Cystine Chapel

Abstract

An animal’s environment contains smaller entities that may attack it and cause illness or death. The immune system evolved to protect against such threats. It has two branches, one innate and the other adaptive. The former relies on field-tested molecules that have been selected over eons. Since they are gene-encoded, these innate molecules are deployed with little or no delay. The adaptive immune system consists of molecular and cellular machinery that produces custom-tailored molecules. Its handiwork is relatively slow, and many clients in need of its products would be lost if their innate systems did not also exist. This chapter focuses on cysteine-containing antimicrobial peptides that contain one or more internal disulfide bonds. Special emphasis is placed on the evolution of two superfamilies of defensins: small, usually cationic and amphipathic host defense molecules with three or four intramolecular disulfide bonds. The ancient roots of both defensin groups predate the advent of adaptive immunity by hundreds of millions of years. One superfamily includes the α-, β-, γ-, and θ-defensins of vertebrates, and the “big defensins” found in cephalochordates, mollusks, and crustaceans. The other superfamily of defensins is expressed in arthropods, mollusks, and fungi and may have arisen much earlier. Like defensins, the evolution of other families of cysteine-containing AMPs can be traced to the predawn of vertebrate existence. Collectively and individually, antimicrobial peptides provide a broad range of protective effects. Yet, despite their essential contributions to animal existence, and perhaps because specificity ranks higher than efficacy in the view of most immunologists, AMPs have often been undervalued. Ironically, it is precisely because AMPs lack specificity that these broadly efficacious molecules have been conserved and refined for more than one billion years.