Retinol-Binding Protein Interferes with Transthyretin-Mediated β-Amyloid Aggregation Inhibition

Biochemistry
Parth Mangrolia, Regina M Murphy

Abstract

β-Amyloid (Aβ) aggregation is causally linked to Alzheimer's disease. On the basis of in vitro and transgenic animal studies, transthyretin (TTR) is hypothesized to provide neuroprotection against Aβ toxicity by binding to Aβ and inhibiting its aggregation. TTR is a homotetrameric protein that circulates in blood and cerebrospinal fluid; its normal physiological role is as a carrier for thyroxine and retinol-binding protein (RBP). RBP forms a complex with retinol, and the holoprotein (hRBP) binds with high affinity to TTR. In this study, the role of TTR ligands in TTR-mediated inhibition of Aβ aggregation was investigated. hRBP strongly reduced the ability of TTR to inhibit Aβ aggregation. The effect was not due to competition between Aβ and hRBP for binding to TTR, as Aβ bound equally well to TTR-hRBP complexes and TTR. hRBP is known to stabilize the TTR tetrameric structure. We show that Aβ partially destabilizes TTR and that hRBP counteracts this destabilization. Taken together, our results support a mechanism wherein TTR-mediated inhibition of Aβ aggregation requires not only TTR-Aβ binding but also destabilization of TTR quaternary structure.

References

Oct 1, 1991·Physiological Reviews·R BlomhoffK R Norum
Feb 28, 1991·Clinica Chimica Acta; International Journal of Clinical Chemistry·G T VatasseryJ H Eckfeldt
Aug 30, 1994·Proceedings of the National Academy of Sciences of the United States of America·A L SchwarzmanP K Coyle
Oct 1, 1993·Annals of Neurology·T WisniewskiB Frangione
Dec 24, 1996·Proceedings of the National Academy of Sciences of the United States of America·G J MiroyJ W Kelly
Sep 18, 1997·Journal of Neuropathology and Experimental Neurology·M C IrizarryB T Hyman
Oct 29, 1997·Journal of Neurology, Neurosurgery, and Psychiatry·J M SerotM Couturier
Aug 15, 2000·Journal of Structural Biology·R M Murphy, M M Pallitto
Apr 11, 2001·Toxicological Sciences : an Official Journal of the Society of Toxicology·W ZhengW S Blaner
Apr 26, 2002·Neuroreport·Pia DavidssonKaj Blennow
Oct 29, 2002·Annals of Neurology·Judith E A WarnerKathleen B Digre
Feb 21, 2003·Biotechnology and Applied Biochemistry·Pullakhandam RaghuBhattiprolu Sivakumar
Jun 16, 2004·Vitamins and Hormones·Giuseppe Zanotti, Rodolfo Berni
Jul 1, 1996·Acta Crystallographica. Section D, Biological Crystallography·A WojtczakW Pangborn
Jan 5, 2005·Journal of Structural Biology·M R H KrebsA M Donald
Apr 27, 2005·Journal of Alzheimer's Disease : JAD·Jing ZhangThomas J Montine
Jun 2, 2005·Neurobiology of Aging·Zhi-Liang WuMary J Savage
Jul 1, 2005·Protein Science : a Publication of the Protein Society·Tony ChristopeitMarcus Fändrich
Sep 27, 2005·Clinical Biochemistry·S GiuntaL Galeazzi
Nov 23, 2005·Biochemistry·Ted R FossJeffery W Kelly
May 30, 2006·Neurobiology of Aging·David A CostaHuntington Potter
Dec 21, 2006·Biochemistry·Lin Liu, Regina M Murphy
Mar 7, 2007·International Review of Cytology·Samantha J Richardson
Jun 29, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Se Hoon ChoiSangram S Sisodia
Dec 20, 2007·Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society·Jenny Libien, William S Blaner
Dec 20, 2007·Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-Ophthalmology Society·Judith E A WarnerPaul S Bernstein
Jan 4, 2008·Pharmaceutical Research·Andrea HaweWim Jiskoot
Feb 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Joel N BuxbaumTamas Bartfai
Feb 27, 2008·Protein Engineering, Design & Selection : PEDS·Bon W KooAndrew D Miranker
Jun 6, 2008·Journal of Alzheimer's Disease : JAD·Sara Friederike GloecknerInga Zerr
Feb 18, 2009·Journal of Alzheimer's Disease : JAD·Sara F HanssonKaj Blennow
Jun 25, 2009·Protein Engineering, Design & Selection : PEDS·Lin LiuRegina M Murphy
Apr 20, 2010·Biochimica Et Biophysica Acta·Matthew Biancalana, Shohei Koide
Jun 17, 2010·Methods in Molecular Biology·Claudia FolliRodolfo Berni

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Citations

Jan 17, 2021·Journal of Pharmaceutical Sciences·Sean E LehmanWyatt N Vreeland
Mar 27, 2021·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Marzieh AraghiEric J Brunner

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