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The Dynamic Composition of the Protein Chaperone Network: Unraveling Human Protein Disaggregation via NMR Spectroscopy

The Dynamic Composition of the Protein Chaperone Network: Unraveling Human Protein Disaggregation via NMR Spectroscopy

Objective

Molecular chaperones are a diverse group of proteins critical to maintaining cellular homeostasis. Aside from protein refolding, it has recently been discovered that certain combinations of human chaperones can break apart toxic protein aggregates and even amyloids that have been linked to a host of neurodegenerative diseases. The first chaperones in this disaggregation reaction that are responsible for recognizing and performing initial remodeling of aggregates, are members of the Hsp40 (DnaJ) and small heat shock protein (sHSP) families. Very little, though, is known regarding how these chaperones perform their functions, and characterization of sHsp- and DnaJ-substrate complexes by most structural techniques has proven extremely challenging, as most chaperones are dynamic in nature and typically operate through a series of transient interactions with both their clients and other chaperones.
The advanced NMR techniques used in our lab, however, are ideally suited for the study of these exact types of dynamic systems, and include recently developed experiments (CEST, CPMG) that allow us to monitor the transient and low populated protein states typical of chaperone-chaperone and chaperone-client interactions, as well as to study the structure of these potentially very large protein complexes (methyl-TROSY).
By exploiting these NMR methodologies and additional, novel labeling schemes, we will characterize, for the first time, the recognition and substrate remodeling performed by the many members of the DnaJ and sHsp chaperone families on their clients. We will then take these approaches one step further and develop real time NMR experiments to observe the client remodeling performed over the course of the disaggregation reaction itself.
By combining advanced NMR with biophysical and functional assays, we ultimately aim to identify the specific sets of chaperones that, with the Hsp70 system, protect our cells by dissolving disease-linked aggregates and amyloid fibers.
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Host institution

WEIZMANN INSTITUTE OF SCIENCE

Address

Herzl Street 234
7610001 Rehovot

Israel

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 499 956

Beneficiaries (1)

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WEIZMANN INSTITUTE OF SCIENCE

Israel

EU Contribution

€ 1 499 956

Project information

Grant agreement ID: 802001

Status

Ongoing project

  • Start date

    1 September 2018

  • End date

    31 August 2023

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 499 956

  • EU contribution

    € 1 499 956

Hosted by:

WEIZMANN INSTITUTE OF SCIENCE

Israel