Please help with this bio chem! 2, Amyloid aggregation (34 points). Amyloid is a
ID: 191909 • Letter: P
Question
Please help with this bio chem!
2, Amyloid aggregation (34 points). Amyloid is a protein associated with Alzheimer's disease that aggregates into repeating sandwich structures. One type of amyloid aggregate involving amino acids 17-41 is shown below in both ribbon and space filling depictions (Luhrs et al. PNAS, 2005) 2 S26 "odd" end V24 F20 N27 25 V18 G29 K28 23 A30 34 A21 V36 F19 131 17 G38 V40 Fibril Axis p1 D23 "odd" end 141 a) Amino acids 26-30 form a loop that connects the two strands. Compare the chemical properties of these sidechains to those of the amino acids 31-41 referencing specific functional groups in your comparison. Is this difference between these two regions expected? Why or why not? (2-3 sentences) b) The K28 sidechain faces into the interior of the sandwich rather than toward the protein exterior. Why would we generally not expect to see a lysine sidechain on the interior of a sandwich? (1 sentence) c) Propose a mutation to amino acid 19 designed to disrupt aggregation of this protein d) Why is the orientation observed for this lysine sidechain favorable in this particular e) D23N mutations have been reported in some people. Would this mutation stabilize f) Some amyloid proteins have glutamate at their N-terminus. An enzyme-catalyzed Justify your choice (1-3 sentences) sheet? (1-3 sentences) or destabilize the structure shown? Justify your answer. (2-3 sentences) dehydration reaction can occur between the sidechain carboxylate and the free amino group to form a five membered ring. Draw the structures of glutamate before and after this dehydration reaction (you can depict the rest of the amyloid protein as g) Experiments in mice suggest that this modification to N-terminal glutamate promotes aggregation of amyloid . Propose an explanation for this observation (2-3 sentences)Explanation / Answer
a) Loop structure : S26 - Serine, N27 - Asparagine, K28 - Lysine, G29 - Glycine, A30 - Alanine
One of beta strand : I31, I32, I41 - Lysine, V36, V39, V40 - Valine, G37, G38 - Glycine, L34 - Leucine, M35 - Methionine
All the amino acids from 31 to 41 are non-polar amino acids because this a buried region or it forms the interior region.
Loop is a exposed or exterior region and therefore it contains polar amino acids (Serine, Asparagine and Lysine). The region 26, 27 and 28 is exposed while 29 and 30 is buried so it contains non-polar amino acids (glycine and alanine)
Yes, this difference is expected because buried or interior region always contains non-polar amino acids and exterior or exposed region contains polar amino acids.
b) K28 - Lysine
Lysine is a positively charged amino acid and it may destabilize the beta sandwich as its side chain faces into the interior. But in this case, it has strong attraction towards D23 to stabilize the structure. Generally, charged amino acid side chains are exposed or faces the exterior region of the protein.
c) F19 - Phenylalanine is a non-polar amino acid. Inorder to destabilize the structure, either positively or negatively charged amino acid can be replaced in place of phenyalanine.
d) Orientation of lysine (Positively charged) stabilizes this structure because it has strong attraction towards D23 (Aspartic acid) which is negatively charged amino acid.
e) When Aspartic acid (D23) is replaced by Asparagine (N), it would destabilize the structure because asparagine is polar uncharged amino acid