Atrial Natriuretic Peptide (ANP): Structure of a 28-Residue Hormone

By What Peptides Editorial Team · Updated 2026-09-14 · Part of Peptide Structure, Classification & Scientific Terminology

Atrial natriuretic peptide is a small cyclic hormone whose structure is unusually easy to describe precisely, which makes it a good object for learning how peptide architecture maps onto function. It circulates as a 28-residue chain held in a large ring by a single disulfide, it is cut out of a much longer precursor, it acts through receptors that are enzymes in their own right, and it is removed from the circulation by two independent routes working at the same time. This page is descriptive physiology written for terminology and structure only. It contains no dose, no schedule, no route, and no recommendation, and it is not a guide to using anything.

The structural facts are checkable in public databases: sequence records carry the precursor length, the signal peptide, the disulfide assignment, and the residue numbering that proteolytic processing produces. What those records give you is architecture, not outcome, and the two should be kept apart. For the vocabulary used below, see our peptide structure and classification reference; for how a chain of this size is actually confirmed in a sample, see how identity is established by mass and chromatography. A related peptide hormone with a different disulfide count, hepcidin, makes a useful contrast.

From a 151-residue precursor to a 28-residue ring

ANP is not synthesized at its final size. The gene is transcribed and translated as preproANP, a 151-residue chain in the human sequence record, whose N-terminal signal peptide directs the nascent chain into the secretory pathway and is removed during translation or shortly after. What remains is the 126-residue prohormone, proANP, which is stored in secretory granules in atrial myocytes and held ready for release. The mature hormone is generated by a single endoproteolytic cut near the C-terminus, carried out by corin, a transmembrane serine protease, which liberates the C-terminal 28 residues as the circulating form.

Those 28 residues carry one disulfide bond, between the cysteines at positions 7 and 23 in mature numbering, and that bond closes a 17-residue ring with short N-terminal and C-terminal tails hanging outside it. The ring is not decoration: opening it by reduction and alkylation removes receptor activation in the classical experiments, because the receptor contacts a conformation that only the cyclic form presents. Using the average residue mass of about 110 Da, a 28-residue chain lands near 3.1 kDa, and the published monoisotopic figure for the human peptide sits in the same region, which is small enough that the molecule is cleared rapidly by renal filtration as well as by enzymatic routes.

Receptors: two cyclases and a clearance receptor

The signaling receptors are single-pass membrane proteins that are enzymes on their inner face. NPR-A, also written GC-A, has an extracellular ligand-binding domain, one transmembrane helix, an intracellular kinase-homology domain that regulates activity, and a C-terminal guanylate cyclase domain that converts GTP to cGMP when the receptor is occupied. NPR-B, or GC-B, is built on the same plan and responds preferentially to a different member of the family. Because the catalytic machinery is part of the receptor itself, there is no separate G protein between occupancy and second messenger production, which is the structural point that distinguishes this class from the seven-transmembrane receptor families.

The third receptor does the opposite job. NPR-C has a large extracellular domain related to the other two but a very short cytoplasmic tail and no cyclase domain; it binds ligand, internalizes constitutively, and returns to the surface, so it acts as a removal route as well as, in some experimental systems, a signaling entity through inhibitory G proteins. The balance between the cyclase-coupled receptors and the clearance receptor is one reason receptor-level descriptions alone cannot predict how long a signal lasts, and it is one of several places where a structural account stops and a physiological one would be needed. cGMP itself is then degraded by phosphodiesterases, which closes the loop at the second-messenger level.

• NPR-A and NPR-B carry their own guanylate cyclase domain and generate cGMP directly.
• NPR-C lacks that domain, internalizes the bound ligand, and is the main removal route at the receptor level.
• The kinase-homology domain regulates cyclase activity rather than phosphorylating the ligand.
• Phosphodiesterases degrade cGMP, so the signal is terminated at the receptor and at the messenger.
• Receptor subtype expression differs by tissue, which is why the same peptide has tissue-specific effects.

Termination: proteolysis and a short circulating half-life

Two enzymatic routes dominate the literature on ANP clearance, and both are structural rather than incidental. Neprilysin, also called neutral endopeptidase or CD10, is a zinc metalloprotease with an extracellular catalytic domain that cleaves the hormone inside the ring; the bond most often reported is between the cysteine and phenylalanine near the N-terminal side of the ring, and cutting there opens the cycle and destroys the receptor-contacting conformation in a single step. Insulin-degrading enzyme has also been described as acting on natriuretic peptides, so the enzymatic picture is one of several overlapping activities rather than a single dedicated peptidase.

The second route is truncation from the N-terminus. Dipeptidyl peptidase-4, or CD26, is an aminopeptidase that removes N-terminal dipeptides from substrates bearing particular penultimate residues, and N-terminal truncation of natriuretic peptides by this enzyme is reported in the literature, producing forms with reduced activity at the cyclase-coupled receptors. Between receptor-mediated internalization, extracellular proteolysis and renal filtration, reported circulating half-lives for the intact hormone are on the order of a few minutes, which is short in absolute terms and entirely typical for an unmodified peptide of this size in plasma.

That combination has a practical consequence for anyone reading the literature rather than the molecule: assays differ in whether they measure the intact hormone, the N-terminal fragment of the prohormone, or both, and pre-analytical handling is a documented source of variability in natriuretic peptide measurement. Two papers can therefore report different values for the same analyte without either being wrong. This page stays at the level of structure and terminology. It makes no claim about any product, states no dose for any person, and is not a guide to testing, interpreting, or acting on a result.

This page is part of the Peptide Structure, Classification & Scientific Terminology guide.