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Hsp70 inhibits aggregation of Islet amyloid polypeptide by binding to the heterogeneous prenucleation oligomers

Neeraja Chilukoti, Bankanidhi Sahoo, S Deepa, Sreelakshmi Cherakara, Mithun Maddheshiya, View ORCID ProfileKanchan Garai
doi: https://doi.org/10.1101/2020.03.30.016881
Neeraja Chilukoti
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
2Centre for Cellular & Molecular Biology, Habsiguda, Hyderabad - 500 007
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Bankanidhi Sahoo
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
3Dr. Reddy’s Laboratories, Bachupally, Hyderabad 500090, India
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S Deepa
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
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Sreelakshmi Cherakara
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
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Mithun Maddheshiya
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
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Kanchan Garai
1Tata Institute of Fundamental Research, 36/P Gopanpally, Serilingampally, Hyderabad 500019, India
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  • ORCID record for Kanchan Garai
  • For correspondence: kanchan@tifrh.res.in
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Abstract

Molecular chaperone Hsp70 plays important roles in the pathology of amyloid diseases by inhibiting aberrant aggregation of proteins. However, mechanism of the interactions of Hsp70 with the amyloidogenic intrinsically disordered proteins (IDPs) is not clear. Here, we use Hsp70 from different organisms to show that it inhibits aggregation of Islet amyloid polypeptide (IAPP) at substoichiometric concentrations even in absence of ATP. The effect is found to be the strongest if Hsp70 is added in the beginning of aggregation but progressively less if added later, indicating role of Hsp70 in preventing primary nucleation possibly via interactions with the prefibrillar oligomers of IAPP. Fluorescence Correlation Spectroscopy (FCS) measurements of the solutions containing fluorescently labelled Hsp70 and IAPP exhibit fluorescence bursts suggesting formation of heterogeneous complexes of oligomeric IAPP binding to multiple molecules of Hsp70. Size exclusion chromatography and field flow fractionation are then used to fractionate the smaller complexes. Multiangle light scattering and FCS measurements suggest that these complexes comprise of monomers of Hsp70 and small oligomers of IAPP. However, concentration of the complexes is measured to be a few nanomolar amidst several μmolar of free Hsp70 and IAPP. Hence, our results indicate that Hsp70 interacts poorly with the monomers but strongly with oligomers of IAPP. This is likely a common feature of the interactions between the chaperones and the amyloidogenic IDPs. While strong interactions with the oligomers prevent aberrant aggregation, poor interaction with the monomers avert interference with the functions of the IDPs.

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Posted March 31, 2020.
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Hsp70 inhibits aggregation of Islet amyloid polypeptide by binding to the heterogeneous prenucleation oligomers
Neeraja Chilukoti, Bankanidhi Sahoo, S Deepa, Sreelakshmi Cherakara, Mithun Maddheshiya, Kanchan Garai
bioRxiv 2020.03.30.016881; doi: https://doi.org/10.1101/2020.03.30.016881
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Hsp70 inhibits aggregation of Islet amyloid polypeptide by binding to the heterogeneous prenucleation oligomers
Neeraja Chilukoti, Bankanidhi Sahoo, S Deepa, Sreelakshmi Cherakara, Mithun Maddheshiya, Kanchan Garai
bioRxiv 2020.03.30.016881; doi: https://doi.org/10.1101/2020.03.30.016881

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