Transthyretin is a metallopeptidase with an inducible active site

The Biochemical Journal
Márcia Almeida LizMónica M Sousa

Abstract

TTR (transthyretin) was found recently to possess proteolytic competency besides its well-known transport capabilities. It was described as a cryptic serine peptidase cleaving multiple natural substrates (including β-amyloid and apolipoprotein A-I) involved in diseases such as Alzheimer's disease and atherosclerosis. In the present study, we aimed to elucidate the catalytic machinery of TTR. All attempts to identify a catalytic serine residue were unsuccessful. However, metal chelators abolished TTR activity. Proteolytic inhibition by EDTA or 1,10-phenanthroline could be reversed with Zn2+ and Mn2+. These observations, supported by analysis of three-dimensional structures of TTR complexed with Zn2+, led to the hypothesis that TTR is a metallopeptidase. Site-directed mutagenesis of selected amino acids unambiguously confirmed this hypothesis. The TTR active site is inducible and constituted via a protein rearrangement resulting in ~7% of proteolytically active TTR at pH 7.4. The side chain of His88 is shifted near His90 and Glu92 establishing a Zn2+-chelating pattern HXHXE not found previously in any metallopeptidase and only conserved in TTR of humans and some other primates. Point mutations of these three residues yielded prot...Continue Reading

References

Apr 1, 1981·The Biochemical Journal·J C SwannW A Galloway
Jan 1, 1981·Methods in Enzymology·A J Barrett, H Kirschke
Oct 1, 1995·Protein Science : a Publication of the Protein Society·D R HollandB W Matthews
May 6, 1997·Biochemistry·G GoldsteinsE Lundgren
Mar 23, 2004·The Journal of Biological Chemistry·Márcia Almeida LizMónica Mendes Sousa
Jul 1, 2004·Environmental Science & Technology·C Marisa R AlmeidaM Teresa S D Vasconcelos
Feb 24, 2005·European Journal of Medicinal Chemistry·Mariangela AgamennoneCarlo Gallina
Dec 3, 2005·The Journal of Biological Chemistry·Pedro Francisco AngeloMaria Aparecida Juliano
Jul 17, 2007·Biochemistry·Lorna E Wilkinson-White, Simon B Easterbrook-Smith
Aug 19, 2007·Journal of Lipid Research·Márcia Almeida LizMónica Mendes Sousa
Jul 30, 2008·Journal of Molecular Biology·Satheesh K PalaninathanJames C Sacchettini
Jan 14, 2009·The Biochemical Journal·Márcia A LizMónica M Sousa
Jul 16, 2009·The Journal of Biological Chemistry·Laura CendronRodolfo Berni
Nov 7, 2009·Nucleic Acids Research·Neil D RawlingsAlex Bateman
Nov 19, 2009·Nucleic Acids Research·Robert D FinnAlex Bateman
Jul 28, 2010·The Journal of Biological Chemistry·Leonardo de C PalmieriDebora Foguel
Apr 20, 2011·Journal of Molecular Recognition : JMR·Ricardo H PiresMiklós S Z Kellermayer

❮ Previous
Next ❯

Citations

Sep 25, 2012·Biochimie·Iuri Estrada GouveaLuiz Juliano
May 12, 2016·Journal of Internal Medicine·M AnkarcronaJ W Kelly
Jul 13, 2016·Journal of Structural Biology·Lidia CicconeWilliam Shepard
Jun 1, 2017·FEBS Letters·Takeshi YokoyamaMineyuki Mizuguchi
Nov 4, 2015·Acta Crystallographica. Section D, Biological Crystallography·Avik BanerjeeKanagaraj Sekar
Feb 3, 2019·British Journal of Pharmacology·Natalia N Nalivaeva, Anthony J Turner
Nov 6, 2014·Biomolecular Concepts·Michael LandrehHans Jörnvall
Mar 22, 2020·International Journal of Molecular Sciences·Tiago GiãoIsabel Cardoso
Sep 15, 2018·Scientific Reports·Lidia CicconeWilliam Shepard
May 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lidia CicconeNicolo Tonali
Dec 2, 2020·International Journal of Molecular Sciences·Natalia Zaręba, Marta Kepinska
Aug 28, 2019·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Adesola Julius TolaPorntip Prapunpoj
Feb 8, 2021·General and Comparative Endocrinology·Kiyoshi Yamauchi
Feb 27, 2020·Biochemistry·Mehdi ShirzadehDavid H Russell
Mar 10, 2021·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Kiyoshi Yamauchi
Mar 1, 2017·General and Comparative Endocrinology·Shunsuke SuzukiKiyoshi Yamauchi
May 1, 2021·International Journal of Molecular Sciences·Laura BianchiM'hammed Aguennouz
Jul 24, 2021·Cellular and Molecular Life Sciences : CMLS·Joana MagalhãesMárcia Almeida Liz

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.