The structure to the right is of a monomer (single unit) of haemoglobin A (HbA) which we examined by chromatography in the practical MDL 1-1. The structure is deduced from the crystallographic studies of Pechik et al and is represented in wireframe mode.
Can you make out the four haem groups?
Clicking on the button below will represent the haem groups as spacefilled, which should make things more evident.
Can you see any elements of secondary structure? Click on the button below.
Like many proteins, haemoglobin also has elements of quaternary structure as it is made up of several subunits. Can you see the separate subunits? Clicking on the button below will colour each subunit a different colour .
Each tetramer is made up of two a and two b chains, predominantly a -helical.
Clicking on the button below will show a model of a sickle haemogobin (HbS) dimer. The structure is deduced from the crystallographic studies of Padlan and Love with the mutant valine residues at position 6 of the b-chains represented as spacefilled molecules.
Where are these residues in relation to the interior/exterior of the molecule?
The buttons below will reveal the highlight the hydrophobic interactions between alanine70 and leucine88 within the beta chain of one monomer and valine6 of another monomer. As the residues are not buried within the protein, but found at the exterior, they are able to readily make hydrophobic interactions with each other. Binding of valine6 to alternative hydrophobic patches may also occur in vivo.
Question:
How might such interactions give rise to the clinical outcomes of sickle cell anaemia?
How might molecular medicine produce a cure for the disease?
Please scroll down for solutions when you have reflected on the questions.
Answer:
Several such hydrophobic interactions can rapidly give rise to a polymers of haemoglobin S which tend to precipitate in solution, thereby distorting the erythrocyte and leading to the characteristic "sickle" shape of the red cell. The major problem in sickle cell disease is occlusion of the blood vessels. Sickled erythrocytes are not flexible and can easily get trapped within narrow capillaries, resulting ultimately in a lack of oxygen to the tissues and infarction/stroke.
Gene therapy (replacement of the gene encoding the sickle form of the beta-chain with one that cannot sickle) offers hope as a future therapy for this disease. In a humanized sickle cell anemia mouse model, Hanna and colleagues were able to rescue mice after transplantation with hematopoietic progenitor stem cells in which the HbS allele had been replaced with HbA by gene-specific targeting.
This page is maintained by James Pease
Based on a template by A. Herráez as modified by J. Gutow.
Page skeleton and JavaScript generated by export to web function using Jmol 12.0.1 2010-07-21 21:46 on 18-Aug-2010
Jmol: an open-source Java viewer for chemical structures in 3D.
http://www.jmol.org