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New Shape of Parkinson's Protein

Evidence reshaping the structure of a protein linked to Parkinson’s suggests a new mechanism for the formation of the disease’s characteristic protein aggregates.

By | August 14, 2011

Possible tetrameric structure of a-synuclein.IMAGE COURTESY OF HARVARD MEDICAL SCHOOL.

New findings, published this week in Nature, challenge the long-standing view that a-synuclein, a protein involved in Parkinson's disease, is a single, unfolded protein. Instead, the protein appears helical in shape, and is composed of four synuclein components. The results suggest an extra step in the process of protein clumping, in which the tetramer first falls apart into its individual protein parts before congealing into the fibrils seen in Parkinson's disease.

The results “really fit with what I was already thinking,” said Julia George, a professor at the University of Illinois, and who was not a researcher on this study. Other groups had previously found evidence that a-synuclein could take shape as a helical tetramer, but the new study is the first to suggest that the helical tetramer might be the most predominant form of the protein in cells. It “strengthens the idea that the helical conformation” is indeed the native form, she said.

The researchers blame the discrepancy between their findings and previous work on a-synuclein on detergents. “We realized that people had always used denaturing methods” to probe the structure of the protein, said Dennis Selkoe, the senior author of the paper and a professor at Brigham and Women's Hospital and Harvard Medical School. The process can break the bonds that knit together a protein's secondary or tertiary structure. “We thought we should try a non-denaturing method,” Selkoe said, but “we didn't know we'd come up with a completely different form.”

When he and his colleagues ran the protein on a non-denaturing gel, which did not include the detergents traditionally used to study the protein, the results suggested that the protein weighed approximately 56 kDafour times the weight of the 14 kDa a-synuclein monomer scientists had previously isolated.

Selkoe's team conducted several other assays to test whether the gel was telling the truth. Robert Edwards, a professor at the University of California, San Francisco, said the most convincing was analytical ultracentrifugation, which characterized the way the protein spun through a solution and confirmed the larger molecular weight.

Selkoe's group also found hallmark signals of a protein wound into a helical formation, suggesting the protein was not unfolded as previously believed.

Still, Edwards said, “it's not that this has completely wiped out our previous understanding” of a-synuclein as an unfolded monomer. It could simply be that both forms of the protein exist at some equilibrium in the cell, agreed Joseph Mazzulli, a research fellow at Massachusetts General Hospital, who was not involved in the research. “I don't know that it's the predominant species,” said Mazzulli, who added that he looks forward to follow up work resolving this question.

But just the realization that the tetramer form of the protein exists in the cell is valuable information towards finally understanding the role of a-synuclein. “The more we know about what synuclein is normally doing, the more we can understand how that is perturbed in Parkinson's disease,” George told The Scientist.

a-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation,” T. Bartels, et al., Nature, doi:10.1038/nature10324, 2011.

 

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Comments

Avatar of: Hilal Lashuel

Anonymous

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of: Hilal Lashuel

Anonymous

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does NOT influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of: Julia George

Anonymous

August 15, 2011

To clarify my statements above, I think that evidence for helical synuclein in cells is consistent with its similarity to other helical lipid-binding proteins, and strengthens my own contention that the helical conformation is the physiologically active form.  However, I think it is premature to conclude from the current results that the helical tetramer is the predominant cellular form, much less the predominant species in neurons of the brain.

Avatar of: Hilal Lashuel

Anonymous

August 15, 2011

I agree with your comment Julia. Also, one must be cautious of estimating the  molecular weight of proteins based on native gels.

Avatar of: help find a cure

Anonymous

August 15, 2011

If you have a computer you could help this research group      http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of:

Posts: 0

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does NOT influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of:

Posts: 0

August 15, 2011

To clarify my statements above, I think that evidence for helical synuclein in cells is consistent with its similarity to other helical lipid-binding proteins, and strengthens my own contention that the helical conformation is the physiologically active form.  However, I think it is premature to conclude from the current results that the helical tetramer is the predominant cellular form, much less the predominant species in neurons of the brain.

Avatar of:

Posts: 0

August 15, 2011

I agree with your comment Julia. Also, one must be cautious of estimating the  molecular weight of proteins based on native gels.

Avatar of:

Posts: 0

August 15, 2011

If you have a computer you could help this research group      http://boinc.bakerlab.org/rose...

Avatar of:

Posts: 0

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of:

Posts: 0

August 15, 2011

This statement is not accurate“We realized that people had always used denaturing methodsâ€쳌 to probe the structure of the protein,The use of denaturing or non-denaturing conditions to purify a-syn  for use in structure studies does NOT influence its final quaternary state , i.e. a-syn produced in E coli is monomeric and unfolded.Hilal A. Lashuel EPFLhttp://lashuel-lab.epfl.ch

Avatar of:

Posts: 0

August 15, 2011

To clarify my statements above, I think that evidence for helical synuclein in cells is consistent with its similarity to other helical lipid-binding proteins, and strengthens my own contention that the helical conformation is the physiologically active form.  However, I think it is premature to conclude from the current results that the helical tetramer is the predominant cellular form, much less the predominant species in neurons of the brain.

Avatar of:

Posts: 0

August 15, 2011

I agree with your comment Julia. Also, one must be cautious of estimating the  molecular weight of proteins based on native gels.

Avatar of:

Posts: 0

August 15, 2011

If you have a computer you could help this research group      http://boinc.bakerlab.org/rose...

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