FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Dailu Chen; Sofia Bali; Ruhar Singh; Aleksandra Wosztyl; Vishruth Mullapudi; Jaime Vaquer-Alicea; Parvathy Jayan; Shamiram Melhem; Harro Seelaar; John C. van Swieten; Marc I. Diamond; Lukasz A. Joachimiak

doi:10.1038/s41467-023-37274-6

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Dailu Chen, Sofia Bali, Ruhar Singh, Aleksandra Wosztyl, Vishruth Mullapudi, Jaime Vaquer-Alicea, Parvathy Jayan, Shamiram Melhem, Harro Seelaar, John C. van Swieten, Marc I. Diamond, Lukasz A. Joachimiak^*

^*Corresponding author for this work

Neurology

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

5 Citations (Scopus)

40 Downloads (Pure)

Abstract

Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the ³⁰⁶VQIVYK³¹¹ amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

Original language	English
Article number	1625
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37274-6
Publication status	Published - 23 Mar 2023

Bibliographical note

Acknowledgements:
L.A.J is supported by a Effie Marie Cain Scholarship in Medical Research and by grants from the BrightFocus Foundation (A2019060S), the Chan Zuckerberg Initiative (CZI) Collaborative Science Award (2018-191983), and the Welch Foundation (I-1928-20200401). S.B. was supported by a fellowship from the National Institutes of Health (NIH) NINDS (F31NS127513). Mass spectrometry experiments were carried out at the UTSW Proteomics core. Transmission electron microscopy was performed at the Electron Microscopy Core Facility at UTSW, supported by the NIH (1S10OD021685-01A1 and 1S10OD020103-01). Computational resources were provided by the BioHPC cluster supported by the Lyda Hill Department of Bioinformatics at UTSW. We would like to thank Andrew Lemoff from the UTSW Proteomics Core for his valuable insights on troubleshooting procedures in crosslinking mass spectrometry. We want to thank Vaibhav Bommareddy for preparing the plasmids of CMV FM5 tauRD WT. We want to thank Bryan Ryder for help with TEM. We appreciate Dr. Paul Seidler for sharing the purification protocol on tauRD and the original WT tauRD plasmid. We thank all members of the Joachimiak lab, in particular Valerie Perez and Bryan Ryder, for discussions and input on the manuscript.

Publisher Copyright: © 2023, The Author(s).

Access to Document

10.1038/s41467-023-37274-6Licence: CC BY

s41467-023-37274-6Final published version, 8.39 MBLicence: CC BY

Cite this

Chen, D., Bali, S., Singh, R., Wosztyl, A., Mullapudi, V., Vaquer-Alicea, J., Jayan, P., Melhem, S., Seelaar, H., van Swieten, J. C., Diamond, M. I., & Joachimiak, L. A. (2023). FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation. Nature Communications, 14(1), Article 1625. https://doi.org/10.1038/s41467-023-37274-6

@article{a53c0f0b3b6942eeb7375086b3593561,

title = "FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation",

abstract = "Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.",

author = "Dailu Chen and Sofia Bali and Ruhar Singh and Aleksandra Wosztyl and Vishruth Mullapudi and Jaime Vaquer-Alicea and Parvathy Jayan and Shamiram Melhem and Harro Seelaar and {van Swieten}, {John C.} and Diamond, {Marc I.} and Joachimiak, {Lukasz A.}",

note = "Acknowledgements: L.A.J is supported by a Effie Marie Cain Scholarship in Medical Research and by grants from the BrightFocus Foundation (A2019060S), the Chan Zuckerberg Initiative (CZI) Collaborative Science Award (2018-191983), and the Welch Foundation (I-1928-20200401). S.B. was supported by a fellowship from the National Institutes of Health (NIH) NINDS (F31NS127513). Mass spectrometry experiments were carried out at the UTSW Proteomics core. Transmission electron microscopy was performed at the Electron Microscopy Core Facility at UTSW, supported by the NIH (1S10OD021685-01A1 and 1S10OD020103-01). Computational resources were provided by the BioHPC cluster supported by the Lyda Hill Department of Bioinformatics at UTSW. We would like to thank Andrew Lemoff from the UTSW Proteomics Core for his valuable insights on troubleshooting procedures in crosslinking mass spectrometry. We want to thank Vaibhav Bommareddy for preparing the plasmids of CMV FM5 tauRD WT. We want to thank Bryan Ryder for help with TEM. We appreciate Dr. Paul Seidler for sharing the purification protocol on tauRD and the original WT tauRD plasmid. We thank all members of the Joachimiak lab, in particular Valerie Perez and Bryan Ryder, for discussions and input on the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

day = "23",

doi = "10.1038/s41467-023-37274-6",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

AU - Chen, Dailu

AU - Bali, Sofia

AU - Singh, Ruhar

AU - Wosztyl, Aleksandra

AU - Mullapudi, Vishruth

AU - Vaquer-Alicea, Jaime

AU - Jayan, Parvathy

AU - Melhem, Shamiram

AU - Seelaar, Harro

AU - van Swieten, John C.

AU - Diamond, Marc I.

AU - Joachimiak, Lukasz A.

N1 - Acknowledgements: L.A.J is supported by a Effie Marie Cain Scholarship in Medical Research and by grants from the BrightFocus Foundation (A2019060S), the Chan Zuckerberg Initiative (CZI) Collaborative Science Award (2018-191983), and the Welch Foundation (I-1928-20200401). S.B. was supported by a fellowship from the National Institutes of Health (NIH) NINDS (F31NS127513). Mass spectrometry experiments were carried out at the UTSW Proteomics core. Transmission electron microscopy was performed at the Electron Microscopy Core Facility at UTSW, supported by the NIH (1S10OD021685-01A1 and 1S10OD020103-01). Computational resources were provided by the BioHPC cluster supported by the Lyda Hill Department of Bioinformatics at UTSW. We would like to thank Andrew Lemoff from the UTSW Proteomics Core for his valuable insights on troubleshooting procedures in crosslinking mass spectrometry. We want to thank Vaibhav Bommareddy for preparing the plasmids of CMV FM5 tauRD WT. We want to thank Bryan Ryder for help with TEM. We appreciate Dr. Paul Seidler for sharing the purification protocol on tauRD and the original WT tauRD plasmid. We thank all members of the Joachimiak lab, in particular Valerie Perez and Bryan Ryder, for discussions and input on the manuscript. Publisher Copyright: © 2023, The Author(s).

PY - 2023/3/23

Y1 - 2023/3/23

N2 - Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

AB - Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.

UR - http://www.scopus.com/inward/record.url?scp=85150876081&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-37274-6

DO - 10.1038/s41467-023-37274-6

M3 - Article

C2 - 36959205

AN - SCOPUS:85150876081

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1625

ER -

FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this