Structure of Haemoglobin

Overview

Haemoglobin (Hb) is a globular, tetrameric protein found in red blood cells. It is the primary oxygen-carrying molecule in vertebrates. Each haemoglobin molecule consists of four subunits, with each subunit made up of a globin polypeptide chain bound to a haem prosthetic group.

Ganong's Review of Medical Physiology - p.557
Guyton and Hall Textbook of Medical Physiology - p.445

1. Quaternary Structure - The Tetramer

Haemoglobin is a tetramer of two pairs of unlike globin polypeptide chains. In normal adult haemoglobin (HbA), these are:

2 alpha (α) chains + 2 beta (β) chains → designated α₂β₂

The four chains fold and fit together to form a compact globular molecule. The arrangement is not symmetric - the alpha and beta chains interact at specific interfaces (α₁β₁ and α₁β₂ contacts), and cooperative oxygen binding depends critically on these inter-subunit contacts.

Haemoglobin structure showing two alpha and two beta chains, each with a central heme group (Histology textbook)

Structural diagram of the haemoglobin molecule - two α-chains (light blue) and two β-chains (purple), each carrying a heme group (pink) with a central iron atom.

2. The Haem Group

Each globin subunit contains one haem prosthetic group embedded in a hydrophobic cleft (pocket) of the polypeptide chain. The folding of the globin chain places haem near the surface, where it is accessible to oxygen.

Haem structure:

A tetrapyrrole porphyrin ring (protoporphyrin IX) with four pyrrole rings (A, B, C, D) joined by methene bridges
A central Fe²+ (ferrous) iron atom coordinated to all four nitrogen atoms of the porphyrin ring
The iron also forms two additional coordination bonds:
- One to the proximal histidine (His F8 / β-His92) - a covalent link anchoring haem to globin
- One to O₂ (or a water molecule in deoxyHb) on the distal side

Heme structure and haemoglobin molecule - (A) the porphyrin ring with central Fe²+ and its polypeptide attachment; (B) the full α₂β₂ tetramer (Guyton & Hall)

Figure A: The heme moiety showing the four pyrrole rings (A-D), central iron atom coordinated to nitrogen atoms of the porphyrin, and attachment to the globin polypeptide. Figure B: The complete haemoglobin tetramer (α₂β₂).

Because there are four haem groups per molecule (one per chain), and each iron can bind one O₂, a single haemoglobin molecule can carry four molecules of O₂ (eight oxygen atoms total). Oxygen binds loosely and reversibly via a coordination bond with iron - it is carried as molecular O₂ (not ionic) and released unchanged in the tissues.

Guyton and Hall Textbook of Medical Physiology - p.445

3. Tertiary Structure - The Globin Chain

Each individual globin chain has a remarkably conserved tertiary structure - virtually all globins (regardless of species or chain type) adopt the same folded conformation called the globin fold:

7-8 helical regions labelled A through H
The haem is held in a hydrophobic pocket between helices E and F
Proximal histidine (His F8 / β-His92) - covalently links haem iron to the protein
Phenylalanine (Phe CD1 / β-Phe42) - wedges the porphyrin ring into the haem pocket; critical for haem retention

Single globin subunit showing the 8 helical regions (A-H) with heme in the pocket, and key residues β-His92 and β-Phe42 (Thompson & Thompson Genetics)

The tertiary structure of a globin subunit: eight helical regions (A-H), with heme (purple) nestled in the pocket between helices. His92 provides the iron-protein covalent link; Phe42 locks the porphyrin in place.

Variants that disrupt helical structure, replace highly conserved residues, or introduce charged groups into the hydrophobic interior invariably produce haemoglobinopathies.

Thompson & Thompson Genetics and Genomics in Medicine - p.252

4. Types of Normal Haemoglobin

All normal human haemoglobins share the α₂X₂ tetrameric plan, but differ in their non-alpha chains. These change during development in a process called globin switching:

Haemoglobin	Chains	Normal Adults	Notes
HbA	α₂β₂	~96%	Predominant adult form
HbA₂	α₂δ₂	1.5-3%	β and δ differ in only 10/146 amino acids
HbF	α₂γ₂	<1%	Fetal form; higher O₂ affinity
HbH	β₄	Pathologic	Forms in severe α-thalassaemia
Embryonic Hbs	ε, ζ chains	Absent after birth	Earliest embryonic haemoglobins

Globin chain synthesis during development showing the switch from fetal HbF (α₂γ₂) to adult HbA (α₂β₂) and HbA₂ (α₂δ₂) around birth (Histology textbook)

Globin switching: In the fetus, γ-chain synthesis produces HbF (60-90%). After birth, β-chain synthesis rises sharply while γ-chains decline, resulting in predominantly HbA (96%) and HbA₂ (<3%) in adults.

Histology: A Text and Atlas - p.685

5. Globin Gene Locations

α-globin genes (α1 and α2) - clustered on chromosome 16 (two copies per haplotype)
β-globin gene cluster (β, δ, γ, ε) - on chromosome 11; genes are arranged in the same order as their developmental expression

6. Clinically Relevant Points

Feature	Significance
Fe²+ state	Must remain ferrous (Fe²+) for O₂ binding; Fe³+ (methaemoglobin) cannot carry O₂
Cooperative binding	Binding of O₂ to one subunit increases affinity of remaining subunits (sigmoid O₂ dissociation curve)
HbA1c	Glucose attached to N-terminal valine of β chains; marker of long-term glycaemic control
Sickle cell (HbS)	Val→Glu substitution at position 6 of β chains; deoxyHbS polymerises into crystals that deform and lyse RBCs
Unstable haemoglobins	Mutations weakening heme-globin linkage, disrupting α-helical structure, or introducing polar residues into the hydrophobic core

Sources: Ganong's Review of Medical Physiology (26th ed.) | Guyton and Hall Textbook of Medical Physiology | Thompson & Thompson Genetics and Genomics in Medicine (9th ed.) | Histology: A Text and Atlas (Pawlina) | Harrison's Principles of Internal Medicine 22E | Robbins, Cotran & Kumar Pathologic Basis of Disease

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