Specific interdomain synergy in the UapA transporter determines its unique specificity for uric acid among NAT carriers

Journal of Molecular Biology
Ioannis PapageorgiouGeorge Diallinas

Abstract

UapA, a uric acid-xanthine permease of Aspergillus nidulans, has been used as a prototype to study structure-function relationships in the ubiquitous nucleobase-ascorbate transporter (NAT) family. Using novel genetic screens, rational mutational design, chimeric NAT molecules, and extensive transport kinetic analyses, we show that dynamic synergy between three distinct domains, transmembrane segment (TMS)1, the TMS8-9 loop, and TMS12, defines the function and specificity of UapA. The TMS8-9 loop includes four residues absolutely essential for substrate binding and transport (Glu356, Asp388, Gln408, and Asn409), whereas TMS1 and TMS12 seem to control, through steric hindrance or electrostatic repulsion, the differential access of purines to the TMS8-9 domain. Thus, UapA specificity is determined directly by the specific interactions of a given substrate with the TMS8-9 loop and indirectly by interactions of this loop with TMS1 and TMS12. We finally show that intramolecular synergy among UapA domains is highly specific and propose that it forms the basis for the evolution of the unique specificity of UapA for uric acid, a property not present in other NAT members.

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Citations

Sep 16, 2011·The Journal of Biological Chemistry·Ekaterini Karena, Stathis Frillingos
Mar 23, 2012·The Journal of Biological Chemistry·Konstantinos Papakostas, Stathis Frillingos
Dec 21, 2013·Fungal Genetics and Biology : FG & B·Emilia Krypotou, George Diallinas
Jul 17, 2010·Fungal Genetics and Biology : FG & B·Cecilia AbreuAna Ramon
Jul 21, 2015·Molecular Microbiology·Ekaterini KarenaStathis Frillingos
Dec 17, 2009·Molecular Microbiology·Christos GournasGeorge Diallinas
Feb 26, 2015·Molecular Microbiology·Emilia KrypotouGeorge Diallinas
Feb 16, 2010·Protein Expression and Purification·James LeungBernadette Byrne
Jul 20, 2016·Trends in Genetics : TIG·G Diallinas
Aug 23, 2008·Journal of Molecular Biology·Ioannis PapageorgiouGeorge Diallinas
Jun 20, 2019·Open Biology·Emmanuel Mikros, George Diallinas
Nov 20, 2016·Biological Chemistry·Yung-Ning Chang, Eric R Geertsma
Aug 19, 2020·The FEBS Journal·Mattia D PizzagalliGiulio Superti-Furga
Dec 4, 2016·Biochemical Society Transactions·Yilmaz AlguelBernadette Byrne
Mar 22, 2020·Molecular Microbiology·Maria BotouStathis Frillingos
Jan 27, 2021·Journal of Molecular Biology·Anezia KourkoulouGeorge Diallinas
Apr 28, 2021·Trends in Biochemical Sciences·George Diallinas
May 2, 2021·FEBS Open Bio·Cristina CecchettiBernadette Byrne
Dec 17, 2008·Science·George Diallinas

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