1. „Top and Tail” — Mr Perwig and Miss Heel (1777)
„London. The year 1777.
An anonymous printmaker publishes a satirical print titled „Top and Tail.” Hand-colored etching with stipple. Signed with fictitious names: „Drawn by Mr Perwig” — Mr Wig. „Engraved by Miss Heel” — Miss High-Heel. Both pseudonyms are jokes. The entire print is a joke.
A figure seen from behind. No face visible. No hands visible. Only mass — an enormous, cylindrical, symmetrical mass of curls surrounding the head. And beneath that mass… bare buttocks. Naked from the waist down. Only stockings with garters and red high-heeled shoes.
Top and Tail. The crown and the rear. The summit and the base.
A satire on the hairstyle madness of the 1770s — and on female vanity that reveals more than it intends. An absurd disproportion between what is on top — monumental, architectural, public — and what is below — naked, exposed, defenseless.
The original is held in the collection of The Metropolitan Museum of Art in New York. The Elisha Whittelsey Collection. Accession number: 59.533.5.
But this print is not a joke.
Or rather — it is a joke that tells the truth. The truth about a structure that no one in 1777 should have known… and yet.”
2. What Are TRP Channels
TRP channels (Transient Receptor Potential — a name referring to the brief electrical signal they produce when activated) are one of the oldest and most important protein families in biology. Think of them as microscopic gates in the wall of a cell — they open and close, letting in charged particles called ions.
Over 30 such gates in mammals. Seven subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, TRPP, TRPN. Each gate opens to a different signal — heat, cold, pain, touch, chemicals.
TRPV1 — a gate that opens above 43°C. It is what makes chili peppers „burn” — capsaicin from chili tricks this gate into opening as if it were hot. Nobel Prize 2021 — David Julius.
TRPM8 — a gate that opens below 26°C. It is what makes mint feel „cool” — menthol tricks this gate into opening as if it were cold.
TRPA1 — the gate for mustard, cinnamon, wasabi. Opens to piercing pain. To frost below 20°C. To the tears from an onion.
TRP channels are molecular thermometers, pain sensors, detectors of touch and pressure. Without them you cannot feel heat. You cannot feel cold. You cannot feel that something hurts.
And TRPC3?
TRPC3 is not a thermometer. TRPC3 is a calcium gate — it lets calcium ions (Ca²⁺) into the cell, where they act as the cell’s internal alarm signal, triggering dozens of processes at once.
TRPC3 works in Purkinje cells in the cerebellum — where it controls motor coordination. A mutation in TRPC3 in the „Moonwalker” mouse causes ataxia — a disorder of motor coordination and balance that makes the mouse move unsteadily and without coordination. In cardiac muscle cells — it regulates contraction. In vascular endothelial cells — it controls blood vessel wall tension. In macrophages (the body’s defense cells) — it regulates the inflammatory response. In lung cells. In kidney cells. In the pituitary gland.
One channel. Dozens of cell types. Hundreds of processes.
When TRPC3 stops working properly — neurodegenerative diseases appear, heart failure, pulmonary hypertension, inflammation, and even cancer.
This is not a marginal protein. This is one of the most important proteins in the body.
And someone drew it in 1777.
3. The TRPC3 Channel — Architecture in Three Layers
PDB: 5ZBG (PDB — Protein Data Bank, a worldwide database where scientists publish the three-dimensional structures of proteins; each structure has its own unique code, just as a book has an ISBN number). Resolution: 4.4 Å. Method: cryo-EM (cryo-electron microscopy — the protein is flash-frozen and photographed with a beam of electrons, allowing its shape to be seen in three dimensions).
The human TRPC3 channel. Four identical copies of the same protein (subunits) join into a ring called a tetramer — like four chairs arranged in a circle, together forming a single „table” with a hole in the middle. That hole is the pore — the channel through which ions flow.
The architecture of TRPC3 is divided into three layers. From top to bottom:
EP — Extracellular Protrusions. Elongated spiral sections of the protein (S3 helices) from each of the four subunits, projecting vertically above the cell surface — like antennas on a rooftop. Unique to the TRPC3/6/7 subgroup — other TRP channels do not have them. In the caricature: the curlers and rolls at the top of the hairstyle.
TMD — Transmembrane Domain. Twenty-four protein spirals (six from each subunit) piercing the cell membrane all the way through — like poles in a wall. Together they form the walls of the ion pore, with two critical elements: the selectivity filter (a sieve that allows only the right ions to pass) and the gate (a door that opens and closes). In the caricature: the dense mass of hair around the head — thick, tight, impenetrable.
CD — Cytoplasmic Domain. The part of the protein hanging inside the cell, beneath the membrane. It contains ankyrin repeats (ARD — protein modules stacked like dominoes, used to connect to other proteins), the TRP helix, and the coiled-coil domain (two or more spirals wound around each other like a braided cord). In the caricature: the buttocks, legs, shoes — everything that hangs below the monumental hairstyle.
The same architectural plan — EP → TMD → CD — applies to the entire TRPC3/6/7 subgroup.
But architecture is not everything. The channel must know when to open and when to close. This decision is made by calcium — the very ion the channel conducts. It is like a door that opens and closes depending on how many people have already passed through.
In 2022, Guo and colleagues (PDB: 7DXB, TRPC3 at 2.7 Å — a nearly twice sharper image than 5ZBG) discovered three calcium-binding sites — CBS1, CBS2, and CBS3 (CBS — Calcium Binding Site, a „socket” into which a calcium ion plugs in like a plug into an outlet) — distributed along the entire height of the channel:
Diagram: Guo W. et al., „Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites,” Neuron, 2022. DOI: 10.1016/j.neuron.2021.12.023)
CBS3 (activating) — in the upper part of the transmembrane domain, in a region called the VSLD (Voltage Sensor-Like Domain — a section of the protein resembling an electrical voltage sensor). When calcium enters this socket — the channel opens. In the caricature: the zone of the rolls.
CBS2 — on the linker between helices in the cytoplasmic domain. A transitional zone.
CBS1 (inhibitory) — in the cytoplasmic domain, between the ankyrin repeats and the helix. When calcium enters this socket — the channel closes. In the caricature: the zone of the buttocks. An intimate site. Hidden. The „private” side of the protein.
The interplay between CBS1 and CBS3 determines the fate of the channel. Activation at the top, inhibition at the bottom. The rolls open. The buttocks close.
And what happens when CBS1 breaks? Certain mutations (changes in the DNA sequence) in the channel TRPC6 — the twin of TRPC3 — destroy the inhibitory CBS1 but preserve the activating CBS3. The channel remains open uncontrollably. Calcium floods in without a brake. Kidney cells die. FSGS develops (focal segmental glomerulosclerosis — damage to the filters in the kidneys, leading to protein loss in urine).
A kidney disease caused by a „broken backside” of a protein.
4. Mapping: „Top and Tail” × 5ZBG
Level 1: Cartoon (rear view)
Cartoon — a way of displaying a protein in the program Mol* (a free tool for visualizing protein structures, available at molstar.org), in which protein spirals (alpha helices) are drawn as thick ribbons and the rest of the chain as thin threads. It resembles a technical drawing — hence the name „cartoon.”
Four subunits arrange themselves around the central axis of the ion pore. Each subunit contributes six spirals piercing the membrane, which together form a dense, compact mass.
But it is not this mass that catches the eye.
At the top — above the membrane — elongated S3 spirals protrude. Characteristic exclusively of the TRPC3/6/7 subgroup. Cylindrical. Symmetrical. Arranged around the central axis like… curlers around a head.
These are Extracellular Protrusions. The Curlers of the Genome.
Below the membrane hang the cytoplasmic domains: ankyrin repeats, TRP helix, coiled-coil. Massive. Loosely hanging. Converging downward into a central bundle.
Top… and Tail.
From top to bottom — element by element:
Red cushion at the top, open like a funnel — the upper pore vestibule (the „waiting room” before the channel entrance). Four P-loops (short sections of the protein chain forming the rim of the entrance) converge from the four subunits and create a funnel-shaped structure — wide at the top, narrowing downward. The entrance to the ion channel from the extracellular side. Calcium ions fall into this funnel from above before reaching the selectivity filter at its bottom. An open, funnel-shaped hair cushion = an open, funnel-shaped entrance to the pore.
Two rolls directly below the cushion — the upper part of the transmembrane domain with the selectivity filter (amino acids I613, F614, G615 — three „blocks” in the protein chain that form a sieve allowing only the right ions through). Helices just below the vestibule, still above the conducting channel proper. A transitional zone — here ions undergo selection. Five acidic (negatively charged) amino acids create an electric field that attracts positively charged calcium ions — like a magnet attracting iron filings.
The braid — central, plaited, running downward — the ion pore itself. Four S6 spirals, one from each subunit, intertwine around a shared axis — like four strands of hair in a braid. The pathway through which calcium ions traverse the membrane. The braid begins below the rolls, not below the cushion — because the conducting channel begins below the filter. Continuous. Plaited. Narrowing.
The end of the braid at the junction with the buttocks — the channel gate. The narrowest point of the pore — amino acid I658, with a radius below 1 Å (less than the diameter of a single atom). The boundary between the transmembrane and cytoplasmic domains. Here the channel opens or closes. Here the braid ends and the nakedness begins.
The buttocks — the cytoplasmic domain. Ankyrin repeats. Massive. Exposed.
Bare legs in red shoes — four alpha spirals of the coiled-coil (wound together like a cord), encoding two legs, hanging straight down.
And the red high-heeled shoes? This remains an open question. At the very end of the coiled-coil spirals, exactly where the shoes sit, lies the CIRB domain (Calmodulin/IP₃ Receptor Binding — the site where calmodulin and the IP₃ receptor bind, two partner proteins that „talk” to the channel and decide whether it should be open or closed). A mere 20 amino acids — 20 blocks out of over 800 in the entire chain. The channel’s point of contact with the outside world. Without this domain the channel cannot even reach the cell membrane — it gets stuck in intracellular compartments. Without shoes, the protein cannot stand where it should. Is this what the red high-heeled shoes encode? If you know the answer — write to us.
The entire caricature is a map of a calcium ion’s journey through the channel — from the funnel (cushion), through the filter (two rolls), through the pore (braid), through the gate (end of the braid), into the cytoplasm (buttocks), along the coiled-coil (legs), all the way to the point of contact with signaling partners (shoes).
Level 2: Surface (rear view)
Surface — a second display mode in Mol*, in which the protein is shown as a solid shape with a smoothed surface — like a clay sculpture instead of a technical drawing.
The contours are soft. Blurred. Thick. Exactly like the inflated, overblown rolls in the „Top and Tail” caricature. No sharpness. No detail. Only mass. Volume. Proportion.
The cushion at the top merges with the rolls beneath it. The braid loses its plaits — becomes a smooth strand running downward. The buttocks lose their contour — a vast, undefined cytoplasmic mass. The legs — the only thing that retains its shape — four alpha coiled-coil spirals protruding straight down.
A naked protein. Stripped of detail. Exposed. Exactly like the figure in the caricature — bare buttocks beneath a monumental hairstyle.
In the „Top and Tail” caricature there are no flowers. No jewelry. No medallions, pearl chains, bows, or feathers — elements that in other Wardrobe of the Genome entries encoded amino acid side chains (small projections sticking out of the protein’s backbone like twigs from a branch), ligands (small molecules that attach to a protein like a key fitting a lock), and post-translational modifications (chemical „ornaments” added to a protein after it has been produced). Compare with the Ditchley Portrait of Elizabeth I, where pearls and chains encoded decorations on the surface of cholera toxin (PDB: 1XTC). Compare with the Pouf à l’Asiatique, where flowers and feathers encoded details of the AMPA receptor (PDB: 6RUQ).
Here there is none of that. The hairstyle is a bare construction — just curlers, just helices, without any ornament. Therefore in this post we will not decode or map at close-up level. The caricature does not show those details — and we decode what we see.
5. Wardrobe of the Genome
As this illustration „Top and Tail” shows, humanity in past centuries encoded proteins in many ways.
On this blog I decode these records. I show how humanity encoded protein structures in material culture. Consciously. With a precision that surpasses modern science — because the details speak for themselves. In heraldry — eagles, lions, and crowns replicate the symmetries and subunits of protein complexes. In sculpture — poses, draperies, and gestures render polypeptide chain folding. In garments — cuts, embroidery, and jewelry replicate domains, motifs, and active sites. In liturgical artifacts — chalices, monstrances, and reliquaries encode receptors and ion channels.
And in hairstyles.
Curlers encoding extracellular protrusions. A braid encoding the ion pore. A cushion encoding the funnel-shaped pore vestibule. Every element in its place. Every proportion faithfully rendered.
But „Top and Tail” goes further than a queen’s portrait or a golden brocade dress.
The anonymous printmaker of 1777 did not merely encode the TRPC3 ion channel with astonishing precision — he did it with humor. He exposed what biology normally hides beneath a layer of lipids (the fats that form the cell membrane). He showed the cytoplasmic domain — that hanging, massive, normally invisible side of a membrane protein — as bare buttocks.
And this is perhaps the deepest joke in the entire history of 18th-century satire.
Because the cytoplasmic domain truly is the „naked side” of a protein. In a living cell — hidden beneath the membrane. Invisible from the outside. Intimate. This is where regulatory interactions take place. This is where kinases (enzymes that switch other proteins on and off), calmodulin (a calcium-sensing protein), and IP₃ (a signaling molecule released when a cell receives a message from its neighbor) bind. This is the „private” side of the channel — the one the cell does not show its neighbors.
Mr Perwig exposed it. He showed the protein’s backside. Literally.
And Miss Heel engraved it, so that everyone could see.
Satire? Yes. A joke? Yes. But a joke that encodes the truth about the structure of a membrane protein with an accuracy that structural biology had to wait another 241 years to achieve — until 2018, when PDB: 5ZBG was published.
They knew. And they had a laugh about it.
But Mr Perwig was not alone. A second version of this caricature exists — French School, 18th century. The same curlers. The same arrangement. But instead of bare buttocks — a skirt with ruffles. Instead of nakedness — clothing.
What does a skirt change in the structure of an ion channel? We will investigate and map it in the next post.
Image search and matching, analysis and elaboration: Tomasz Mikulski – Cell God: 07/2026
Illustration sources: „Top and Tail” — Anonymous, British, 18th century. 1777. Hand-colored etching with stipple. The Metropolitan Museum of Art, New York. The Elisha Whittelsey Collection, 59.533.5. https://www.metmuseum.org/art/collection/search/391903
Protein structures: RCSB Protein Data Bank — 5ZBG. Visualization: Mol (molstar.org).
