Step 1 · Biochemistry

Cell Biology & Signaling

Name: Cell Biology & Signaling
Creator: Veli Bakalov, MD

From collagen to G proteins: the cell's scaffolding and switches

Biochemistry·Cellular·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Collagen types: I bone, skin, tendon (osteogenesis imperfecta); II cartilage, vitreous, nucleus pulposus; III reticulin and vessels (vascular Ehlers-Danlos); IV basement membrane (Alport, Goodpasture).
Collagen synthesis: Gly-X-Y chains in the RER → vitamin C–dependent proline/lysine hydroxylation → triple-helix procollagen → propeptide cleavage to tropocollagen → copper-dependent lysyl oxidase cross-linking.
Osteogenesis imperfecta (type I collagen, usually AD): fractures from minimal trauma, blue sclerae, conductive hearing loss, opalescent teeth — can mimic child abuse.
Menkes disease (X-linked ATP7A) causes copper deficiency, low lysyl oxidase activity, kinky hair, hypotonia; contrast Wilson disease (ATP7B, copper overload).
Intermediate filament markers: vimentin (mesenchyme), desmin (muscle), cytokeratin (epithelium), GFAP (glia), neurofilament (neurons).
Kinesin is anterograde and dynein retrograde; defective dynein arms cause Kartagener syndrome (situs inversus, sinusitis, bronchiectasis, infertility).
Taxanes hyperstabilize microtubules; vinca alkaloids, colchicine, mebendazole, and griseofulvin interfere with polymerization and spindle function.
The Na+/K+-ATPase pumps 3 Na+ out and 2 K+ in per ATP; digoxin and ouabain inhibit it, raising intracellular Ca2+ and contractility.
Gs (β1, β2, D1, H2, V2) raises cAMP, Gi (M2, α2, D2) lowers it, and Gq (α1, M1, M3, H1, V1) drives PLC, IP3, DAG, and Ca2+; cholera toxin locks Gs on and pertussis toxin disables Gi.

Collagen and elastin

Collagen types. Collagen is the body's main structural protein, built from Gly-X-Y repeats (X and Y are often proline and lysine). Four types carry most of the clinical weight: type I bone, type II cartilage, type III blood vessels, type IV basement membrane.

Collagen types

Type	Where	Linked disease
I (about 90%)	Bone, skin, tendon	Osteogenesis imperfecta
II	Cartilage, vitreous, nucleus pulposus	Cartilage and eye disorders (e.g., Stickler syndrome)
III	Reticulin, blood vessels	Vascular Ehlers-Danlos
IV	Basement membrane	Alport syndrome (defective); Goodpasture (autoantibodies)

Synthesis. Collagen is assembled partly inside the fibroblast and partly outside it, and each step has a signature disease.

RER: preprocollagenGly-X-Y α chains are translated
HydroxylationProline and lysine residues; needs vitamin C (scurvy)
Glycosylation → procollagenThree chains wind into a triple helix (defective in osteogenesis imperfecta)
Exocytosis + cleavageTerminal propeptides removed, giving tropocollagen
Cross-linkingCopper-dependent lysyl oxidase (impaired in Menkes and some Ehlers-Danlos types)

Collagen synthesis

Elastin. Rich in nonhydroxylated proline and glycine, elastin gives stretch to the lungs, large vessels, and skin. Lysyl oxidase cross-links it through desmosine. Elastase degrades it and is held in check by α1-antitrypsin, whose deficiency leaves elastase unopposed (emphysema). Fibrillin (FBN1) forms the scaffold for elastin and is defective in Marfan syndrome.

Connective tissue disorders

Osteogenesis imperfecta. Usually a type I collagen defect (COL1A1/COL1A2), most often autosomal dominant. Findings: multiple fractures after minimal trauma, blue sclerae (thin, translucent sclera reveals the choroidal veins), conductive hearing loss, and opalescent teeth. It can be mistaken for child abuse.

Ehlers-Danlos syndrome. Faulty collagen gives hyperextensible skin, hypermobile joints, and easy bruising. The hypermobility type is most common; the vascular type (type III collagen) is the dangerous one, risking arterial, uterine, or bowel rupture.

Menkes disease. X-linked recessive defect of the copper transporter ATP7A causes copper malabsorption and deficiency. Lysyl oxidase activity falls, so collagen and elastin cross-linking fails: brittle, kinky, depigmented hair, growth retardation, and hypotonia, with low serum copper.

Menkes = ATP7A (copper deficiency); Wilson disease = ATP7B (copper overload).

Cytoskeleton and motor proteins

Microfilaments (actin). Drive muscle contraction and cytokinesis.

Intermediate filaments. Provide structural support; because each cell lineage uses its own filament, they serve as immunohistochemical markers of a tumor's origin:

Vimentin — mesenchymal (connective tissue) cells
Desmin — muscle
Cytokeratin — epithelium (carcinomas)
GFAP — glial cells
Neurofilament — neurons

Microtubules. Hollow polymers of α/β-tubulin dimers that bind GTP. They form cilia, flagella, and the mitotic spindle and serve as rails for axonal transport. Kinesin carries cargo anterograde (toward the plus end and the synapse); dynein carries it retrograde (toward the minus end and the cell body) — the route rabies virus and tetanus toxin use to reach the CNS.

Cilia and Kartagener syndrome. Cilia have a 9+2 microtubule arrangement bent by axonemal dynein. In Kartagener syndrome (primary ciliary dyskinesia) the dynein arms are defective: situs inversus, chronic sinusitis, bronchiectasis, and infertility from immotile sperm.

Drugs that act on microtubules

Drug	Use	Action
Mebendazole	Helminths	Blocks polymerization
Griseofulvin	Dermatophyte fungi	Disrupts the mitotic spindle
Colchicine	Gout	Blocks polymerization; impairs neutrophil chemotaxis
Vincristine, vinblastine	Cancer	Block polymerization, arresting mitosis
Paclitaxel (taxanes)	Cancer (e.g., breast)	Hyperstabilizes microtubules so the spindle cannot disassemble

Mnemonic: Microtubules Get Constructed Very Poorly (Mebendazole, Griseofulvin, Colchicine, Vinca alkaloids, Paclitaxel).

Taxanes and vinca alkaloids both stop mitosis but in opposite ways: taxanes freeze microtubules; vinca alkaloids (and colchicine) prevent them from forming.

The Na+/K+-ATPase

Stoichiometry. Each ATP hydrolyzed pumps 3 Na+ out of the cell and 2 K+ in, maintaining the ion gradients that set the resting membrane potential.

3 Na+ out / 2 K+ inPer ATP hydrolyzed

Inhibitors. Ouabain binds the pump's K+ site. Cardiac glycosides such as digoxin also inhibit it: intracellular Na+ rises, the Na+/Ca2+ exchanger slows, intracellular Ca2+ accumulates, and myocardial contractility increases.

G protein–coupled signaling

Three main G proteins. Gs stimulates adenylyl cyclase, raising cAMP, which activates protein kinase A (PKA); Gi inhibits adenylyl cyclase, lowering cAMP; Gq activates phospholipase C, which cleaves the membrane lipid PIP2 into IP3 (releases Ca2+ from the endoplasmic reticulum) and DAG (activates protein kinase C).

G proteins and their receptors

G protein	Pathway	Receptors
Gs	↑ adenylyl cyclase → ↑ cAMP → PKA	β1, β2, D1, H2, V2
Gi	↓ adenylyl cyclase → ↓ cAMP	M2, α2, D2
Gq	Phospholipase C → IP3 (↑ Ca2+) + DAG (PKC)	α1, M1, M3, H1, V1

Memory aids: "MAD 2's" are Gi (M2, α2, D2); "HAVe 1 M and M" is Gq (H1, α1, V1, M1, M3).

Toxins that hijack cAMP. Cholera toxin locks Gs in the "on" state, so cAMP rises in intestinal cells and drives a profuse secretory (rice-water) diarrhea. Pertussis toxin disables Gi, removing the brake on adenylyl cyclase — cAMP rises by the opposite route.

Clinical example. Vascular smooth-muscle α1 receptors are Gq-coupled: IP3 releases Ca2+ from the endoplasmic reticulum, producing vasoconstriction.