MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions

Yuichi Yoshimura; Mats Holmberg; Predrag Kukic; Camilla Bertel Andersen; Alejandro Mata-Cabana; S. Fabio Falsone; Michele Vendruscolo; Ellen A.A. Nollen; Frans Mulder

doi:10.1074/jbc.M116.764886

MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions

Yuichi Yoshimura, Mats Holmberg, Predrag Kukic, Camilla Bertel Andersen, Alejandro Mata-Cabana, S. Fabio Falsone, Michele Vendruscolo, Ellen A.A. Nollen, Frans Mulder

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

34 Citations (Scopus)

Abstract

Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with α-synuclein (α-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated α-helix that interacts with the negatively charged C terminus of α-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of α-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it.

Original language	English
Journal	Journal of Biological Chemistry
Volume	292
Issue	20
Pages (from-to)	8269-8278
Number of pages	10
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M116.764886
Publication status	Published - 19 May 2017

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Journal Article

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10.1074/jbc.M116.764886

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title = "MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions",

abstract = "Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with α-synuclein (α-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated α-helix that interacts with the negatively charged C terminus of α-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of α-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it.",

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MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions. / Yoshimura, Yuichi; Holmberg, Mats; Kukic, Predrag et al.
In: Journal of Biological Chemistry, Vol. 292, No. 20, 19.05.2017, p. 8269-8278.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions

AU - Yoshimura, Yuichi

AU - Holmberg, Mats

AU - Kukic, Predrag

AU - Andersen, Camilla Bertel

AU - Mata-Cabana, Alejandro

AU - Falsone, S. Fabio

AU - Vendruscolo, Michele

AU - Nollen, Ellen A.A.

AU - Mulder, Frans

PY - 2017/5/19

Y1 - 2017/5/19

N2 - Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with α-synuclein (α-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated α-helix that interacts with the negatively charged C terminus of α-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of α-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it.

AB - Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with α-synuclein (α-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated α-helix that interacts with the negatively charged C terminus of α-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of α-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it.

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MOAG-4 promotes the aggregation of α-synuclein by competing with self-protective electrostatic interactions

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