His protects heme as it crosses the membrane

Abstract

From the multitude of proteins with bound prosthetic groups, metal clusters, or cofactors, the soluble c-type cytochromes were among the first to be characterized, probably because of their spectral visibility and unusual stability. The pathway for their biosyntheses, nevertheless, remains to be filled in as do the mechanistic details of holoprotein formation. Historically, many assumed, perhaps naively, that the assembly of most metallo- or other cofactor-containing proteins occurred without catalysis, relying on spontaneity, and this idea was reinforced by the facile in vitro formation of stable FeS clusters and uncatalyzed in vitro reconstitution of metalloproteins like plastocyanins or ferredoxins from inorganic ions and apoproteins. Today, we appreciate that synthesis of a functional holoprotein is a biochemical pathway with multiple catalyzed steps that ensure selectivity and specificity. Because the c-type cytochromes contained covalently bound heme, the need for catalysis for their biosynthesis was always appreciated and indeed genetic analyses over the last 30 years have revealed a striking diversity of pathways, of which the so-called system I, II, and III pathways are the most common (reviewed in refs. 1 and 2). Their unifying features include a requirement for reductant and a heme binding component. In this issue of PNAS, Frawley and Kranz (3) demonstrate that the conserved WWD motif of the CcsBA protein of the system II pathway is a heme binding platform on a transmembrane protein that serves to deliver heme from the bacterial cytoplasm to the periplasm.