A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells

International Journal of Molecular Sciences
Marie Nicole BongiovanniMichele Vendruscolo

Abstract

Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet β-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the speci...Continue Reading

References

Jul 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·P WestermarkC Betsholtz
Apr 1, 1996·Current Opinion in Biotechnology·G Georgiou, P Valax
Jan 8, 1999·Journal of Molecular Biology·C GoldsburyG J Cooper
Aug 15, 2000·Journal of Structural Biology·C GoldsburyU Aebi
Feb 24, 2001·Annals of the New York Academy of Sciences·J NylandstedM Jäättelä
Dec 20, 2003·Nature·Christopher M Dobson
Mar 27, 2004·The Journal of Biological Chemistry·Jochen KluckenPamela J McLean
Jul 24, 2004·Nature Medicine·Christopher A Ross, Michelle A Poirier
Dec 22, 2004·Nature Reviews. Neuroscience·Paul J Muchowski, Jennifer L Wacker
Jan 27, 2005·The Journal of Biological Chemistry·Matthew M DedmonChristopher M Dobson
Mar 17, 2005·Cellular and Molecular Life Sciences : CMLS·M P Mayer, B Bukau
Sep 22, 2005·Nature Reviews. Cancer·Luke Whitesell, Susan L Lindquist
Feb 4, 2006·Molecular Cell·Markus VogelMatthias P Mayer
May 9, 2006·Cell·Bernd BukauArthur Horwich
Jul 20, 2006·American Journal of Physiology. Endocrinology and Metabolism·Juris J MeierPeter C Butler
Sep 16, 2006·The Journal of Biological Chemistry·Christopher G EvansJason E Gestwicki
Jan 25, 2007·Nature Reviews. Molecular Cell Biology·Christian Haass, Dennis J Selkoe
Feb 16, 2008·Science·William E BalchJeffery W Kelly
Mar 7, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Virginia L VegaAntonio De Maio
Apr 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maarten F M EngelJo W M Höppener
May 13, 2008·Angewandte Chemie·Rajesh MishraRoland Winter
Jan 29, 2010·The New England Journal of Medicine·Henry W Querfurth, Frank M LaFerla
Mar 2, 2010·Nature Reviews. Drug Discovery·Adriano Aguzzi, Tracy O'Connor
Apr 1, 2010·Molecular Neurobiology·Tom Z LuZhong-Ping Feng
Oct 15, 2010·CNS & Neurological Disorders Drug Targets·S K KaliaP J McLean
Oct 15, 2010·Nature Reviews. Molecular Cell Biology·Jens TyedmersBernd Bukau
Jul 22, 2011·Nature·F Ulrich HartlManajit Hayer-Hartl
Aug 26, 2011·The Journal of Biological Chemistry·Saurabh Trikha, Aleksandar M Jeremic
Dec 21, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mazin Magzoub, Andrew D Miranker
Mar 20, 2012·Cell·David Eisenberg, Mathias Jucker
Apr 23, 2013·BioMed Research International·Karen Pillay, Patrick Govender
Dec 10, 2013·Acta Neuropathologica Communications·Darius Ebrahimi-FakhariLara Wahlster

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Citations

Oct 10, 2018·Chemical Society Reviews·Pietro SormanniMichele Vendruscolo
Sep 13, 2018·International Journal of Molecular Sciences·Sofia GiorgettiFrancesco Antonio Aprile
Sep 16, 2020·Biophysics Reviews·Gaurav Pandey, Vibin Ramakrishnan
Jan 9, 2021·Biophysical Journal·Neeraja ChilukotiKanchan Garai
Sep 28, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Noeli Soares Melo SilvaJúlio César Borges
Oct 13, 2021·Journal of Cellular Physiology·Carine MarmentiniMirian A Kurauti

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Datasets Mentioned

BETA
NP005336

Methods Mentioned

BETA
fluorescence titration assay
transmission electron microscopy

Software Mentioned

GraphPad
Prims

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