The clinic where you are an intern regularly treats a number of patients with Si

Question

The clinic where you are an intern regularly treats a number of patients with Sickle Cell Anemia. This disease is caused b my a single amino acid change in one of the polypeptide subunits of hemoglobin, a cytosolic protein found in red blood cells which binds of the protein abnormality that lead to symptoms are represented in your patient population. Look at the figure below which shows the amino acid change for these three variants, as well as a picture of normal and disease hemoglobin.
28) 5 pts. The clinic where you are an intern regularly treats a number of patients caused by a single amino acid change in one of the pohraentides blood.ce three known variants of the protein abnormality that lead to symptons are at the figure below which shows the amino acid change for these three variants, as diseased hemoglobin. with Sickle represented in your patient popotacion. Looi well as a picture of normal and Amino acid position (ot 146) 2 67 16 24 26 56 63 95 A His Glu Glu Gy Gly Glu Gly His Lys TokuchiTy Val Lys ia NORMAL HEMOGLOBIN sickled, clumped HEMOGLOBIN at aming acid position 6 result in clinical abnormality A) Why does a change from Glutamic Acid (Glu) to Váline (Val) (this the classic change found in most sickle cell patients, called variant$1 whereasa change from Hist Tyrosine at position 2 does not (variant Tokuchil)? Note that both amino acids 2 and 6are found on the surface of the protein. Also note that normal hemoglobin amino acids are shown in line A of the amino acia A

Explanation / Answer

A) When there is a glutamic acid to valine substitution in position 6 in beta chain (b6), there is decreased solubility of Haemoglobin (Hb) due to polymerization of Hb tetramers. Hb is a tetramer of 2 alpha and 2 beta chain. Polymerization of deoxy-Hb S occurs due to hydrophobic interactions between b6 valine residues on one tetramer and the hydrophobic EF acceptor pocket (between e and F helices involving phenylalanine and leucine) of an adjacent tetramer. The b6 valine side chain inserts into this hydrophobic pocket. Hydrophobiciity and stereospecificity of valine. Glutamic acid on the other hand, is hydrophillic and does not form this interaction witj the hydrophobic pocket on another tetramer.

The surface amino acids are hydrophilic as they are associated with the water environment. In the Hb Tokuchi, histidine is replaced by tyrosine. Histidine is hydrophilic while tyrosine is hydrophobic. Tyrosine is uncharged. Steriospecificity plays an important role in interaction with the EF acceptor pocket. Tyrosine cannot interact with the EF acceptor pocket due to the presence of an aromatic ring. Hence, despite replacement with hydrophobic amino acids, glu-valine replacement allows polymerization while His-Tyr does not. Infact, addition of bulky side chain inhibits interaction with EF acceptor pocket and prevents polymerization.

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