An Extra Arm May Impair the Open Hand

In the paper, “Inhibin Biosynthesis and Activity Are Limited by a Prodomain-Derived Peptide,” Walton et al (1) purport that processing of inhibin-α can result in a 43-amino acid pro-α peptide from an alternate cleavage site. This propeptide is projected to have an amphipathic α-helical structure that can wrap around the open hand or butterfly-shaped mature inhibin protein, thereby hindering inhibin association with β-glycan. The function of this proinhibin α-peptide is investigated as an inhibitor of mature inhibin action. The inhibins and activins are produced as prepro-proteins in which nonactive domains that are important to protein folding and dimerization of the molecules are cleaved, releasing the final active products. The β-subunits for inhibin and activin have only one classical cleavage site, but the α-inhibin subunit has another cleavage site between the pro-α-peptide and the N-peptide (Figure 1A). Uncleaved or incompletely cleaved inhibins have been described for many years as high-molecular-weight or big inhibins, with varying demonstrations of bioactivity (2,–4). A free α-subunit in association with the C portion, without the N portion, has also been described and is produced at high levels by a variety of normal and abnormal tissues (5, 6), but this is the first evaluation of a functional small prodomain cleavage peptide for inhibin. Figure 1. A, Inhibin precursor with the cleavage sites. Note the two cleavage sites on the α-subunit and the single cleavage site on the β-subunit. B, Inhibin A/B binding to β-glycan. C, Pro-α-peptide intercalating between inhibin ... The authors also noted some time ago that three hydrophobic amino acids in the prodomain of the inhibin α-subunit were critical to proper folding and secretion of mature inhibins (7). In that work they used mutagenesis evidence to propose a model of interaction of the N-terminal prodomain with a region near the C terminus of the proprotein to hold it in a coiled conformation that would allow the covalent bonds with the similarly held β-proprotein subunits and promote further processing. In that work they also proposed that the entire cleaved prodomain could remain associated with the active inhibin in a noncovalent way, such as the fact that the latency-associated peptide remains associated with TGFβ (8). In this work they have focused on the role of the small 43-amino acid propeptide. Not only do they demonstrate the necessity of cleavage of this promolecule from the N and C regions of inhibin for production of mature peptide to occur, but they also provide strong evidence for a role of this unassuming peptide in modulating the bioactivity of the mature inhibins. Yet it does not seem to interfere with activin activity. Thus, inhibin protein may come along with its own tiny inhibitor after processing, with the little associated prodomain peptide intercalating itself between the interface with inhibin A or B and the β-glycan receptor (Figure 1, B and C). Yet a function of β-glycan is to inhibit the activation of the activin receptor signaling cascade (9, 10). So the inhibitor is packaged with its own inhibitor, like a functional mini-me, providing direct modulation of inhibin function. This has profound implications biologically if this relationship is shown to occur in vivo. Activin action is already known to be tightly regulated on many levels, both directly and indirectly. From the expression of excess inhibin α-subunits (favoring inhibin production over activin), to follistatin or α-macroglobin binding, to production of inhibitory smads that can directly modulate the activin signaling cascade; the action of activin is tightly regulated in tissue-specific ways, and its effects are profoundly concentration and tissue specific (11, 12). Entry into this already complex system regulating activin, the action of a small amphipathic molecule that could be delivered to a specific site to block inhibin and thereby increase activin action and possibly result in increased unbound β-glycan may have great usefulness clinically and as a research tool across several overlapping fields of endocrinology.