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Spinocerebellar ataxia 3 (SCA3) is a neurodegenerative disease that manifests as a progressive decrease in coordination of limbs and frequently results in impaired speech and eye coordination. It is associated with extension of the polyglutamine (polyQ) region of the ataxin-3 protein. The polyQ region is encoded by a series of consecutive CAG codons known as poly-CAG repeats. These regions vary in length from one person to another, ranging from as few as 10 to as many as 80 repeats. SCA3 has been reported in patients with polyQ regions exceeding ~55 repeats, and increased polyQ length correlates with earlier onset of the disease and greater clinical severity.Circular dichroism (CD) is a method of assessing protein secondary structure. It measures a molecule's ability to absorb left- and right-handed circularly polarized light of varying wavelengths. The absorption difference is known as "ellipticity," denoted by Δε. Alpha-helices have a maximum Δε at 190 nm, and beta-sheets have a maximum Δε at 200 nm.CD results show that as the length of the ataxin-3 polyQ region increases, alpha-helical nature is lost and the protein aggregates, ultimately precipitating out of solution and depositing in brain and other tissues. Furthermore, as proteins aggregate, they form beta-sheets. These beta-sheets are in the parallel orientation, and each sheet can interact with sheets in other proteins to form long, insoluble structures known as amyloid fibers (Figure 1) .
Figure 1 Depiction of the ataxin-3 polyQ region shifting from alpha-helical (cylinders) to beta-sheet (arrows) structure and aggregatingGlutamine can be encoded by both CAG and CAA codons. Researchers investigated survival rates in fruit flies expressing ataxin-3 with polyQ regions of equal length encoded by either CAG-CAG or CAA-CAG repeats (Table 1) . The protein products had identical amino acid sequences.Table 1 Fruit Fly Survival Rates Relative to Ataxin-3 Expression
Adapted from Bevivino AE, Loll PJ. An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta -fibrils. Proc Natl Acad Sci USA. 2001;98(21) :11955-60.
-Which of the following could increase the stability of the beta-conformation of long polyglutamine regions?

Question

Passage
Spinocerebellar ataxia 3 (SCA3) is a neurodegenerative disease that manifests as a progressive decrease in coordination of limbs and frequently results in impaired speech and eye coordination. It is associated with extension of the polyglutamine (polyQ) region of the ataxin-3 protein. The polyQ region is encoded by a series of consecutive CAG codons known as poly-CAG repeats. These regions vary in length from one person to another, ranging from as few as 10 to as many as 80 repeats. SCA3 has been reported in patients with polyQ regions exceeding ~55 repeats, and increased polyQ length correlates with earlier onset of the disease and greater clinical severity.Circular dichroism (CD) is a method of assessing protein secondary structure. It measures a molecule's ability to absorb left- and right-handed circularly polarized light of varying wavelengths. The absorption difference is known as "ellipticity," denoted by Δε. Alpha-helices have a maximum Δε at 190 nm, and beta-sheets have a maximum Δε at 200 nm.CD results show that as the length of the ataxin-3 polyQ region increases, alpha-helical nature is lost and the protein aggregates, ultimately precipitating out of solution and depositing in brain and other tissues. Furthermore, as proteins aggregate, they form beta-sheets. These beta-sheets are in the parallel orientation, and each sheet can interact with sheets in other proteins to form long, insoluble structures known as amyloid fibers (Figure 1) .

Figure 1 Depiction of the ataxin-3 polyQ region shifting from alpha-helical (cylinders) to beta-sheet (arrows) structure and aggregatingGlutamine can be encoded by both CAG and CAA codons. Researchers investigated survival rates in fruit flies expressing ataxin-3 with polyQ regions of equal length encoded by either CAG-CAG or CAA-CAG repeats (Table 1) . The protein products had identical amino acid sequences.Table 1 Fruit Fly Survival Rates Relative to Ataxin-3 Expression

Adapted from Bevivino AE, Loll PJ. An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta -fibrils. Proc Natl Acad Sci USA. 2001;98(21) :11955-60.
-Which of the following could increase the stability of the beta-conformation of long polyglutamine regions?

Quizplus · Accepted Answer

11ecba2d_0de7_4ea7_a3bf_e923a5ac54d9_MD0008_00 In each strand of a beta-sheet, the amino acid side chains project out from and perpendicular to the backbone in alternating opposite directions. As beta-sheets form, the R groups become aligned. Glutamine is a polar uncharged amino acid with an amide side chain. Amides contain both a carbonyl oxygen and an amide nitrogen group, which can act as a hydrogen bond acceptor and donor, respectively. Because the side chains are aligned in beta-sheets and because glutamine can simultaneously act as an acceptor and a donor, polyglutamine beta-sheets can form networks of hydrogen bonds. These networks add stability to the beta-sheet conformation, so increased polyglutamine length increases hydrogen bond networks and stabilizes the beta-conformation. (Choice A) Stacking interactions can indeed stabilize secondary structures. However, they only occur between aromatic side chains such as phenylalanine, tyrosine, and tryptophan. (Choice B) It is glycine, not glutamine, whose flexibility is favorable for beta-turns. (Choice C) The rigidity of proline, along with its tendency to adopt the cis-conformation, is conducive to tight turns. However, glutamine is not particularly rigid. Educational objective: Aligned glutamine side chains in adjacent strands of beta-sheets can hydrogen bond with each other because they can act as both donors and acceptors. Polyglutamine beta-sheets can form networks of side-chain hydrogen bonds, adding considerable stability to the beta-structure.

Passage Spinocerebellar Ataxia 3 (SCA3) Is a Neurodegenerative Disease That Manifests