Cortisol-signaling fragment of ACTH (residues 22: 39)

What this is

ACTH [22-39] is an 18-residue fragment spanning the C-terminal segment of adrenocorticotropic hormone (ACTH), the 39-amino-acid pituitary hormone that drives cortisol production in the adrenal glands. The full-length ACTH molecule is itself cleaved from a larger precursor protein called proopiomelanocortin (POMC), which serves as the source of multiple distinct peptide hormones depending on where and how it is processed (Harno and colleagues 2018). This particular fragment — residues 22 through 39 of that full sequence — has been detected as a naturally occurring processing intermediate in pituitary tissue (Che and colleagues 2005) and is used in research as a tool to probe the structural requirements of the MC2R (melanocortin 2 receptor), the adrenal receptor through which ACTH exerts its steroidogenic effects.

History

ACTH's structure was characterized in the early 1950s, and work on the functional boundaries of the molecule — which parts are needed for adrenal activity and which are not — followed in subsequent decades. Uhler and colleagues (1983) established that the mouse genome contains two non-allelic POMC genes, contributing to the foundational understanding of POMC biology and the variety of fragments it produces. The peptidomics era provided direct evidence that the pituitary generates a broader array of POMC-derived fragments than classical biochemistry had captured: quantitative peptidomics work in Cpe(fat/fat) mice, which carry an inactivating mutation in the carboxypeptidase E gene, revealed multiple POMC intermediates including fragments covering the C-terminal ACTH region (Che and colleagues 2005). The biology of the melanocortin receptor family — five GPCRs with overlapping ligand profiles — has been systematically reviewed as interest in selective agonists has grown; MC2R stands apart as the only melanocortin receptor that responds exclusively to full-length ACTH rather than to the shorter melanocyte-stimulating hormone peptides (Fridmanis and colleagues 2017).

What it does

The fragment covers the region of ACTH that lies outside the established melanocortin core: the N-terminal HFRW motif (residues 6-9 of ACTH) is the conserved binding pharmacophore shared by all melanocortin peptides, while the C-terminal region of ACTH contributes to the unique selectivity of full-length ACTH for MC2R over the other four melanocortin receptors. This makes the [22-39] segment a tool for dissecting what structural elements confer that selectivity. In vivo, MC2R activation by ACTH drives steroidogenesis in the adrenal cortex: receptor engagement raises intracellular cAMP, activates protein kinase A, and stimulates the StAR protein that shuttles cholesterol into the mitochondria — the rate-limiting step of cortisol synthesis. Chida and colleagues (2007) generated MC2R knockout mice and demonstrated that MC2R is required not only for adrenal steroidogenesis but also for normal adrenal gland development and neonatal gluconeogenesis. ACTH [22-39] itself does not replicate the full agonist activity of intact ACTH at MC2R; its value lies in characterizing which receptor-binding contacts are located in this region.

Evidence

• Human: No human studies of this isolated fragment. Research on the C-terminal region of ACTH is conducted at the biochemical and cellular level to define MC2R binding determinants.
• Animal: MC2R knockout mice established the essential in vivo role of the receptor in adrenal development and cortisol production (Chida and colleagues 2007). Peptidomics of mouse pituitary tissue identified this fragment as a naturally occurring POMC processing intermediate (Che and colleagues 2005).
• In vitro: The question of what elements of ACTH are required for MC2R specificity has been examined through receptor binding and mutagenesis studies reviewed in Fridmanis and colleagues (2017), which specifically addresses the molecular mechanisms underlying MC2R's unusually strict ACTH selectivity among the five melanocortin receptors.

Known effects

• MC2R specificity probe — Research use; no established pharmacological effect as an isolated fragment
• Naturally occurring POMC processing intermediate — Detected in pituitary peptidomics (Che and colleagues 2005); biological significance of endogenous levels is uncharacterized

Mechanism

MC2R is a class A GPCR that differs from the other four melanocortin receptors in requiring the full ACTH sequence for activation — it does not respond to α-MSH or other short melanocortin peptides. The basis for this selectivity is an active area of research. Fridmanis and colleagues (2017) review evidence that the C-terminal region of ACTH, beyond the shared melanocortin core, makes contacts with MC2R that are necessary for high-affinity binding and receptor activation, and that these contacts explain why MC2R does not respond to truncated melanocortins that activate MC1R, MC3R, MC4R, and MC5R. The ACTH [22-39] fragment covers this C-terminal specificity region. The receptor is expressed predominantly on adrenocortical cells and signals through Gαs-coupled cAMP elevation to activate the protein kinase A pathway and StAR-mediated steroidogenesis. The broader melanocortin receptor system — and the consequences of mutations across all five MCR genes — is surveyed in Switonski and colleagues (2013) and Cai and colleagues (2016).

Open questions

• What specific contacts does the [22-39] region make with MC2R, and are they sufficient for any partial agonism or do they function only in the context of the full 39-residue molecule?
• Whether naturally occurring POMC processing intermediates covering this region have biological activity independent of full-length ACTH
• Structural basis for MC2R's unique ACTH selectivity compared to the other four melanocortin receptors remains incompletely resolved (Fridmanis and colleagues 2017)

Related peptides

The full-length ACTH precursor and its better-characterized fragments are documented in the platform's melanocortin and POMC family cards. The POMC processing landscape — which peptides are generated in which tissues — is reviewed comprehensively in Harno and colleagues (2018).