Sickle Cell Anemia: Secondary & Tertiary Structure Change?

[kite718]

In sickle-cell anemia, does the mutation to a valine cause a change in the secondary or tertiary structure of the protein?

 

[edvinf]

This page: http://www.umass.edu/microbio/chime/hemoglob/2frmcont.htm

seems to have a vizualisation of both structures, but I could not open it my browser.

I did try to compare the pdb structures of both healthy and sick Hb (4HHB and 2HBS) and to me it does not look like the secondary and tertiary structures around the mutation are changed much. Could not the Valine itself provide the necessary extra hydrophobicity to form the aggregate ?

 

[kite718]

Hi,

Thanks for the info... see I found information on the primary structure - so i figured it the primary structure changes that must mean the secondary and tertiary structure changes too. Am I wrong with this thinking?

 

[kite718]

doesn't the changes in the secondary and tertiary structure affect the quaternary structure?

 

[Ygggdrasil]

Changes in the primary structures of proteins do not necessarily change the secondary or tertiary structures of proteins. Furthermore, changes in the secondary and tertiary structures of proteins can occur without changing the primary structure (e.g. by adding a small molecule or another protein that interacts with the protein).

Perhaps it would be useful to start with some basics: do you know what causes red blood cells to become sickle-shaped in sickle cell anemia?

 

[kite718]

ohh ok...i see.

The mutation in the hemoglobin beta gene is substituted with a valine, which is a hydrophobic residue. The molecules of hemoglobin residue which clump together forming a sickle shaped cell.

 

[edvinf]

If you are getting examined in this I would be a little bit elaborate :-).

doesn't the changes in the secondary and tertiary structure affect the quaternary structure?

In general changes at a low structural level propagate upwards (so that the higher levels also are changed), but not necessarily much. Some structures are very sensitive to certain single-residue substitutions, while many such substitutions will produce only negligible changes in the higher level structures. It seems to me that the Glutamate-Valine substitution in Hemoglobin is one substitution that pretty much preserves the secondary and tertiary structure.

The hydrophobic path created by the Valine (or probably more importantly by the removal of Glutamate) causes the area around this residue to interact favorably with another hydrophobic path of other Hemoglobins, causing the "clumping togheter" that you describe. So the mutation does affects the higher order structure of the Hemoglobin(s), although the secondary and tertiary level is not much changed (I am not sure whether it is correct to refer to aggregation as quaternary structure, but it is definitely a form of high-order structure).

 

[kite718]

thank you so much for your help!