What Do Peptides Do? Biological Roles of Peptides

Peptides are among the most versatile molecules in biology. Short chains of amino acids carry messages between cells, defend organisms against microbes, guide newly made proteins to the right compartment and help buffer the chemical environment inside cells. So what do peptides do? In most cases they act as signals or recognition elements: they bind a receptor, a membrane or another protein with high specificity, trigger a response, and are then degraded quickly once their job is done.

This article surveys the main biological roles of endogenous peptides and then looks at how laboratories use synthetic peptides as research tools. For the underlying chemistry of amino acids, peptide bonds and chain length, start with our primer on what peptides are and how they are built.

Peptide Hormones: Messengers of the Endocrine System

Many hormones are peptides. Endocrine cells synthesise them as larger precursors, store them in secretory granules and release them by exocytosis in response to a specific stimulus. Once in the circulation they travel to distant tissues and bind receptors on the outer surface of target cells. Because peptides are generally too polar to cross the lipid bilayer, the signal is relayed inside the cell by receptor-coupled machinery: G proteins and second messengers such as cyclic AMP and calcium, or the phosphorylation cascades of receptor tyrosine kinases.

The structures involved vary widely. Oxytocin and vasopressin are nonapeptides with a six-residue ring closed by a disulfide bond, made in the hypothalamus and released from the posterior pituitary. Glucagon is a 29-residue linear peptide from pancreatic alpha cells. Insulin consists of an A chain of 21 residues and a B chain of 30, joined by two interchain disulfide bonds after processing from single-chain proinsulin. Glucagon-like peptide-1 (GLP-1) is cut from the same proglucagon precursor as glucagon, but in intestinal L cells and by a different processing enzyme; it acts on a class B G protein-coupled receptor and is rapidly inactivated by dipeptidyl peptidase-4. That short lifetime is typical, and it gives peptide signals tight control in time.

Hypothalamic releasing peptides

Some of the smallest hormones act close to their source. Thyrotropin-releasing hormone is a modified tripeptide (pyroglutamyl-histidyl-prolinamide), and gonadotropin-releasing hormone is a decapeptide with similar terminal blocking groups that protect it from exopeptidases. Upstream of GnRH neurons, kisspeptins derived from the KISS1 gene act on the KISS1 receptor, a G protein-coupled receptor once known as GPR54. These releasing peptides travel only a short distance, through the portal vessels linking the hypothalamus to the anterior pituitary.

Neuropeptides: Modulators of Neural Circuits

Neurons release peptides as well as classical small-molecule transmitters. Neuropeptides are packaged in large dense-core vesicles rather than the small synaptic vesicles used for transmitters such as glutamate, are often co-released with them during high-frequency firing, and act mostly on G protein-coupled receptors. They work at lower concentrations and over longer distances and timescales than fast transmitters, so they are usually described as modulators rather than direct carriers of synaptic signals.

Substance P, an 11-residue tachykinin acting at the neurokinin-1 receptor, and the enkephalins, two pentapeptides (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu) that bind opioid receptors, were among the first to be characterised. Neuropeptide Y, with 36 residues, is one of the most abundant peptides in the mammalian brain. Their production follows a common route: a precursor is cleaved at pairs of basic residues by prohormone convertases, trimmed by carboxypeptidase E, and often C-terminally amidated by peptidylglycine alpha-amidating monooxygenase, a modification many neuropeptides need for full receptor activity.

Antimicrobial Peptides: Innate Host Defence

Plants, insects, amphibians and mammals all produce antimicrobial peptides (AMPs). Most are short, roughly 12 to 50 residues, carry a net positive charge from lysine and arginine, and adopt amphipathic structures with hydrophobic and cationic faces. That arrangement lets them bind the negatively charged surfaces of bacterial membranes in preference to the outer leaflet of animal cell membranes. Proposed mechanisms include barrel-stave pores, toroidal pores and a detergent-like carpet model, and some AMPs act on intracellular targets instead. Defensins (small peptides with three disulfide bonds), the cathelicidin LL-37 and the magainins first isolated from the African clawed frog Xenopus laevis are well-studied families, with most mechanistic evidence coming from in vitro membrane models and bacterial cultures.

Growth Factors, Signal Peptides and Other Roles

Growth factors

At the larger end of the size range, polypeptide growth factors regulate cell proliferation and differentiation. Insulin-like growth factor 1 is a 70-residue single chain with three disulfide bonds that signals through a receptor tyrosine kinase, and epidermal growth factor is a 53-residue polypeptide acting at its own receptor tyrosine kinase. Synthetic versions of several endogenous peptides, including oxytocin and kisspeptin discussed above and the 28-residue thymic peptide thymosin alpha-1, are listed in our laboratory peptide catalog as in vitro research materials.

Signal peptides

Not every peptide acts as a free molecule. Signal peptides are N-terminal sequences, typically 15 to 30 residues with a hydrophobic core, that direct newly made secretory and membrane proteins into the endoplasmic reticulum or, in bacteria, across the plasma membrane. The signal recognition particle binds the sequence as it emerges from the ribosome, and signal peptidase removes it once targeting is complete. Work by Günter Blobel and colleagues in the 1970s established this signal hypothesis.

Redox buffering and bacterial communication

Glutathione, the tripeptide γ-glutamyl-cysteinyl-glycine, is present at millimolar concentrations in many cells and serves as the main thiol redox buffer. In Gram-positive bacteria, short peptides act as quorum-sensing signals: Staphylococcus aureus, for example, secretes autoinducing peptides closed by a thiolactone ring that report population density to neighbouring cells.

How Laboratories Use Peptides as Research Tools

Because peptides can be synthesised to exact sequences, they are among the most widely used reagents in molecular and cell biology. Synthetic hormone and neuropeptide analogues serve as receptor agonists and antagonists in cell-based assays measuring cyclic AMP accumulation, calcium flux or arrestin recruitment, and concentration–response curves from such assays yield potency values such as EC₅₀. Our guide to cell signaling assays describes these readouts, and the article on peptide receptor binding covers the principles behind them.

Peptides have many other bench roles. Fluorogenic peptide substrates, such as a DEVD sequence coupled to a fluorescent leaving group for caspase-3, report enzyme activity. Short epitope tags such as FLAG (DYKDDDDK) and HA (YPYDVPDYA) are fused to proteins for detection and purification. Peptides conjugated to carrier proteins are used as antigens to raise sequence-specific antibodies, and stable isotope-labelled peptides act as internal standards in quantitative mass spectrometry. Cell-penetrating sequences such as the HIV-1 TAT (47–57) fragment are studied as tools for delivering cargo into cultured cells. Researchers sourcing reference compounds from our research peptides range should confirm identity and purity on the lot certificate of analysis before use. These materials are for laboratory research use only and are not for human or veterinary use.

Peptide Biology in Brief

Across these examples, a pattern emerges. Peptides carry information: hormones and neuropeptides between cells, antimicrobial peptides against microbial membranes, signal peptides within the cell’s own protein-sorting machinery. They are typically made from larger precursors, tailored by specific enzymes, active at receptors or membranes at low concentrations, and short-lived. Those same properties of precise sequence, defined binding and ready synthesis are what make peptides such useful tools in the research laboratory.

References

1. Nelson DL, Cox MM. Lehninger Principles of Biochemistry. W. H. Freeman.
2. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002, 415, 389–395.
3. Hökfelt T, et al. Neuropeptides: an overview. Neuropharmacology 2000, 39, 1337–1356.
4. Drucker DJ. The biology of incretin hormones. Cell Metabolism 2006, 3, 153–165.
5. Blobel G, Dobberstein B. Transfer of proteins across membranes. I. Journal of Cell Biology 1975, 67, 835–851.