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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.
-Why might ataxin-3 aggregates become insoluble?

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.
-Why might ataxin-3 aggregates become insoluble?

Quizplus · Accepted Answer

11ecba2d_0de8_ae38_a3bf_89a7c98ea050_MD0008_00 Disruption of a protein's native conformation may force exposure of hydrophobic residues to the aqueous environment. Hydrophobic residues are unable to form hydrogen bonds with water, so when they are exposed to an aqueous environment, water molecules are forced to form a rigid network to satisfy hydrogen bond requirements. These interactions are thermodynamically unfavorable. To avoid these unfavorable interactions, hydrophobic molecules aggregate to decrease the total surface area exposed to water. This phenomenon, known as the hydrophobic effect, is a driving force in protein folding. Hydrophobic residues are normally buried in the protein core to minimize exposure to the surrounding aqueous environment. As the alpha-helices of ataxin-3 are converted to beta-sheets, the protein must undergo an overall conformational change. This change may prohibit hydrophobic residues from being buried, and may expose them to water. This in turn can cause the hydrophobic residues of multiple proteins to aggregate, to the exclusion of water. By definition, the inability to interact with a solvent (water, in this case) is insolubility. (Choice B) Glutamine has an uncharged polar side chain. It has no ionic interactions to disrupt. (Choice C) The interaction of glutamine side chains with each other does not prevent their interaction with water. Hydrogen bonds between side chains may transiently break to bond with water, and vice versa. (Choice D) Peptide backbones are not very hydrophobic because they have both a carbonyl and an amino group that can form hydrogen bonds. Educational objective: Proteins that adopt non-native conformations are generally forced to expose more hydrophobic residues to the aqueous environment. These residues cannot interact with water, and therefore tend to aggregate to minimize exposure due to the hydrophobic effect. Inability to interact with water results in precipitation out of solution.

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