Freitag, 03. November 2017, 10:00 - 11:30 iCal
Prof. Dijkstra Bauke W.
Laboratory of Biophysical Chemistry, University of Groningen, Holland
"Crystal structure of human tyrosinase related protein 1 reveals an active site with a type 3 zinc-binding site and provides a structural explanation for albinism causing mutations"
Im Rahmen des Biophysikalisch Chemischen Kolloquiums
Seminarraum 2C505 im UZA II
Althanstraße 14, 1090 Wien
Vortrag
Crystal structure of human tyrosinase related protein 1 reveals an active site with a type 3 zinc-binding site and provides a structural explanation for albinism causing mutations
Bauke W. Dijkstra1,*, Xuelei Lai1,2, Montserrat Soler-Lopez2,
and Harry J. Wichers3
1Laboratory of Biophysical Chemistry, University of Groningen, The Netherlands
2ESRF-The European Synchrotron, Grenoble, France
3Laboratory of Food Chemistry, Wageningen University, The Netherlands
*Corresponding author: b.w.dijkstra@rug.nl
Melanin is the pigment responsible for the pigmentation of skin, eye, and hair in humans. Its production in melanocytes requires the activity of at least three melanogenic glycoenzymes, tyrosinase (TYR), and tyrosinase-related proteins 1 (TYRP1) and 2 (TYRP2). Limited structural information has hampered the understanding of the reaction and substrate specificity of the different enzymes, as well as the molecular basis of the pathological mutations related to oculocutaneous albinism and hyperpigmentation disorders. We succeeded in heterologously expressing TYR and TYRP1 in insect cells, and purifying and crystallizing them. X-ray crystal structures were elucidated of wild-type and mutant TYRP1, which revealed a typical tyrosinase fold and a Cys-rich subdomain that is unique to vertebrate melanogenic proteins. It contains two zinc ions as metal cofactors, as opposed to tyrosinase, which contains two copper ions. In contrast to previous assumptions, human TYRP1 does not show hydroxylase nor oxidase activities, although a low level of these activities can be conferred to the enzyme by replacing zinc by redox-active copper ions. The presence of zinc suggests that TYRP1 may catalyze a protonation/deprotonation reaction, generating a phenolate intermediate that may be further oxidized by tyrosinase. Crystal structures of TYRP1 with bound tyrosinase substrates and inhibitors show similar ligand binding modes as in other tyrosinases. The crystal structure of TYRP1 provides a structural rationalization of oculocutaneous albinism type 3 related mutations, which can provide insights into the mechanisms of the disease and guide structure-based design of compounds for pigmentation disorder treatments.
Lai, X., Soler-Lopez, M., Wichers, H. J. & Dijkstra, B. W. (2016). Large-scale recombinant expression and purification of human tyrosinase suitable for structural studies. PLoS ONE 11, Article Number e0161697.
Lai, X., Soler-Lopez, M., Wichers, H. J. & Dijkstra, B. W. (2017). Structure of human tyrosinase TYRP1 reveals a binuclear zinc active site important for melanogenesis. Angew. Chem. Int. Ed. 56, 9812 –9815.
Veranstalter
Fakultät für Chemie, Institut für Biophysikalische Chemie
Kontakt
Brigitte Schwarz
Fakultät für Chemie der Universität Wien
Dekanat
01/4277-52006
brigitte_schwarz@univie.ac.at
Erstellt am Mittwoch, 20. September 2017, 15:09
Letzte Änderung am Montag, 25. September 2017, 08:34