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Linus Pauling said sickle-cell anemia might be caused by a __
· Sickle cell anemia results from the __ that form __.
specific variation in the amino acid sequence of one hemoglobin chain
- aggregation of mutated deoxyhemoglobin molecules
- large fibrous aggregates
These fibers extend across the RBCs, distorting them so that they __ and __, leading to __, __ or __, and __
Caused by a __ The mutated form is hemoglobin S
, which substantially decreases the __of deoxyhemoglobin
- clog small capillaries and impair blood flow
- painful swelling, risk of stroke or bacterial infection, anemia
single amino acid substitution in the beta chain of hemoglobin—replacement of valine with glutamate in position 6.
Examination of the structure of hemoglobin S reveals that the new valine residue lies __--> interacts with __ of a neighboring moleculeà
More detailed analysis reveals that a single hemoglobin S fiber is formed from __
- on the surface of the T-state molecule
- another hydrophobic patch on the B chain
- 14 chains of multiple interlinked hemoglobin molecules
They do not form when hemoglobin S is __. Without a partner, the Val residue in position 6 is benign
One copy of the HbB gene are unaffected but have the trait, which makes them resistant to malaria
oxygenated because oxyhemoglobin S is in the R state, and residues Phe 85 and Val 88 on the Beta chain are largely buried inside the hemoglobin assembly
· __is caused by an imbalanced production of hemoglobin chains
Caused by the __---> result?
- loss or reduction of a single hemoglobin chain
- low levels of functional hemoglobin and a decreased production of BCs
Examination of the human genome has revealed two additional globins, both of which are monomeric proteins, more similar to myoglobin than to hemoglobin. WHat are they?
in the brain and retina; play a role in protecting neural tissues from hypoxia
more expressed throughout the body
In both, the proximal and distal histidines are coordinated to be iron atom in the deoxy form. Oxygen binding displaces the distal histidine.
- o Neuroglobin: in the brain and retina; play a role in protecting neural tissues from hypoxia
- o Cytoglobin: more expressed throughout the body
In both neuroglobin and cytoglobin, what?
the proximal and distal histidines are coordinated to be iron atom in the deoxy form. Oxygen binding displaces the distal histidine.
In alpha-thalassemia, the alpha chain of hemoglobin is not produced in sufficient quantity. Consequently, hemoglobin tetramers form that contain only the B chain. These tetramers, called Hemoglobin H (HbH), bind oxygen with high affinity and no cooperatively. Thus, oxygen release in the tissues is poor.
§ In B-thalassemia, the B chain of hemoglobin is not produced in sufficient quantity. In the absence of B chains, the alpha chains form insoluble aggregates that precipitate inside immature red blood cellsà anemia (worst kind: Cooley anemia)
§ Both a- and B- thalassemia are associated with different genetic variations and display a wide range of clinical severity. Why?
· Normally, humans have four alleles for the alpha chain, arranged such that the two genes are located adjacent to each other on one end of each chromosome 16. Thus, the complete loss of alpha-chain expression requires the disruption of four alleles. B-thalassemia is more common because humans normally have only two alleles for the B chain.
· The accumulation of free alpha-hemoglobin chains is prevented even though there are four alpha-hemoglobin chains and only 2 B-chains
o One mechanism for maintaining alpha chains in solution was revealed by the discovery of an __ in RBCs called __, which forms a soluble complex specifically with newly synthesized alpha-chain monomers
11-kd protein in RBCs called alpha-hemoglobin stabilizing protein
§ The crystal structure of a complex between AHSP and alpha hemoglobin reveals that __
§ AHSP binds the alpha chain both the __. In the complex with oxygen bound, the __, rather than the __, binds the iron atom.
AHSP binds tot eh same face alpha hemoglobin as does B-hemoglobin.
de- and oxygenated forms.
- distal histidine, rather than the proximal histidine
§ AHSP serves to bind and ensure the proper folding of __ as it is produced. As B-hemoglobin is expressed, it does what? Thus, AHSP prevents the __, __, __ of __
- displaces AHSP alpha-hemoglobin-AHSP complex
- misfolding, accumulation, and precipitation of free alpha-hemoglobin