Protein Chemistry, Enzyme function, and Cell signaling. A paper published in 200
ID: 302080 • Letter: P
Question
Protein Chemistry, Enzyme function, and Cell signaling. A paper published in 2008 analyzed the kinase domains of the EGFR and HER2 (Human EGFR 2).
The graph below looks at the activity of wild type and mutant forms of HER2. Again, these mutations are in the kinase domain of the protein.
a. Based on the results below the effects of each mutation Increase (increase or decrease; 2pts) the relative activity of the HER2 kinase (ErbB2(712-1255)).
b. Fill in the blank below with the chemical character of each amino acid:
G:__________________ (1pt)
S:__________________ (1pt)
D:_________________ (1pt)
c. Link your understanding of the chemistry involved in proper protein folding/conformation with your understanding of enzymatic function to HYPOTHESIZE why the relative activity of G776S/G778D double mutant has changed. (HINT: how might the mutation make the kinase domain function better?) Rubric (4): Use understanding of protein chemistry (possible effects of the mutation on folding/conformation; 2pts) to a specific effect on enzyme function (hypothesis that would that lead to the result) (2pts).
t forms of HER2. Again, these mutations 120 80 40 ar ErbB2 (712-1255 c function to HYPOTHESIZE why the ged (HINT: how might the mutation make g of protein chemistry (possible effects of the mutation on hat would ha lead to the u ptsExplanation / Answer
Answer: (a) Each mutation increases the relative activity as compared to the wild-type.
(b): G is Glycine. It has aliphatic side chain, and is nonpolar and neutral in nature. pI is 6.06
S is Serine. It has hydroxyl side chain, and is polar and neutral in nature. pI is 5.68
D is Aspartic acid. It has acidic side chain, and is acidic polar and negative in nature. pI is 2.98
(c): The conformation of protein which is resultant of protein folding is very important for the proper functioning of a protein. The number and sequence of amino acids in the polypeptide chain is crucial for its proper folding. Protein folding of an enzyme takes places in a manner to carry out proper relay of electron flow and various electrostatic interactions between the molecule during biochemical reaction, and hence positioning of each amino acid is very crucial. The hydrophobic patches are kept at the interior and the polar pathches are exposed so that they can form interaction with the aqueous solution of cell.
The pI value of S and D are not similar, therefore, at a given pH of cell (i.e. 7 approx.) D has positive charge and S is nearly neutral. This combination either hinder the formation of various interactions or hinders the relay of electron flow. That is why, double mutant showed altered (incresed to be precise) activity.
(d): Upn mutation, Protein no longer folds in similar manner.. Its conformation has changed to some extent due to change in the amino acid sequence on mutation. The protein involved in autoinhibition, now no longer is able to inhibit itself as it cannot interact with the site due to changes in functional domain. Therefore, on mutation, the level of expression increased many folds.
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