Sickle Cell Anemia: Secondary & Tertiary Structure Change?

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Discussion Overview

The discussion revolves around the structural changes in hemoglobin associated with sickle cell anemia, specifically focusing on whether the mutation to valine affects the secondary or tertiary structure of the protein. Participants explore the implications of primary structure changes on higher-order protein structures and the mechanisms behind the sickling of red blood cells.

Discussion Character

  • Exploratory
  • Technical explanation
  • Debate/contested

Main Points Raised

  • One participant questions whether the mutation to valine causes changes in the secondary or tertiary structure of hemoglobin.
  • Another participant notes that their comparison of pdb structures for healthy and sick hemoglobin suggests minimal changes in secondary and tertiary structures, proposing that valine may contribute hydrophobicity necessary for aggregation.
  • A participant expresses uncertainty about the relationship between primary structure changes and their effects on secondary and tertiary structures.
  • There is a suggestion that changes in secondary and tertiary structures could influence quaternary structure, although this is debated.
  • One participant asserts that primary structure changes do not necessarily lead to changes in secondary or tertiary structures and that such changes can occur independently.
  • Another participant explains that the hydrophobic nature of valine contributes to hemoglobin aggregation, leading to sickle-shaped cells, while also discussing the potential preservation of secondary and tertiary structures despite the mutation.
  • There is a discussion about whether aggregation should be classified as a quaternary structure change, with some uncertainty expressed about this classification.

Areas of Agreement / Disagreement

Participants express differing views on the extent to which the mutation affects secondary and tertiary structures, and there is no consensus on whether aggregation should be classified as a quaternary structure change. The discussion remains unresolved regarding the implications of primary structure changes on higher-order structures.

Contextual Notes

Participants reference specific protein structures and mutations, but there are limitations in the discussion regarding the assumptions made about structural changes and the definitions of structural levels.

kite718
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In sickle-cell anemia, does the mutation to a valine cause a change in the secondary or tertiary structure of the protein?
 
Biology news on Phys.org
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 ?
 
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?
 
doesn't the changes in the secondary and tertiary structure affect the quaternary structure?
 
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?
 
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.
 
If you are getting examined in this I would be a little bit elaborate :-).

kite718 said:
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).
 
thank you so much for your help!
 

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