SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

Ben A. Meinen; Varun V. Gadkari; Frederick Stull; Brandon T. Ruotolo; James C.A. Bardwell

doi:10.1073/pnas.1913316116

SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

Ben A. Meinen, Varun V. Gadkari, Frederick Stull, Brandon T. Ruotolo, James C.A. Bardwell

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer's and Parkinson's patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF's high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.

Original language	English (US)
Pages (from-to)	23040-23049
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	46
DOIs	https://doi.org/10.1073/pnas.1913316116
State	Published - Nov 12 2019
Externally published	Yes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.).

Funding Information:
We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.).

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

Keywords

Alzheimer's
Chaperone
Protein folding

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10.1073/pnas.1913316116

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title = "SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins",

abstract = "The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer's and Parkinson's patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF's high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.",

keywords = "Alzheimer's, Chaperone, Protein folding",

author = "Meinen, {Ben A.} and Gadkari, {Varun V.} and Frederick Stull and Ruotolo, {Brandon T.} and Bardwell, {James C.A.}",

note = "Funding Information: ACKNOWLEDGMENTS. We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.). Funding Information: We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",

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AU - Gadkari, Varun V.

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AU - Bardwell, James C.A.

N1 - Funding Information: ACKNOWLEDGMENTS. We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.). Funding Information: We thank Sheena Radford for helpful advice, Dr. Michael Cianfrocco and Dr. Tony Ludlam for assistance in performing the electron microscopy experiments, and Ke Wan in the J.C.A.B. laboratory for protein purification. This work was funded by the Howard Hughes Medical Institute, at which J.C.A.B. is an Investigator. This work was also supported by the University of Michigan Protein Folding Diseases Initiative and the Agilent Thought Leader Award Program (B.T.R.). Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.

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N2 - The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer's and Parkinson's patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF's high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.

AB - The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer's and Parkinson's patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF's high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.

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ER -

SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

Abstract

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