Priority Programme: THYROID TRANS ACT
Translation of Thyroid Hormone Actions beyond Classical Concepts

Dr. Anita Kinne, Dr. Gerd Krause

Role of the L-type amino acid transporter Lat2 in transport of thyroid hormones

Thyroid hormones (TH) and its derivatives are transported across the cell membrane into and out of the cell by diverse transmembrane transporter proteins, e.g. by members of the monocarboxylate transporter (MCT) and of the L-type amino acid transporter (LAT) families.

Studies of Lat2 in the mouse brain indicated that Lat2 is also crucial in TH transport. Substrate specificity and first structural implications were shown only for the TH specific transporter MCT8 (Kinne et al. JBC 2010). The fact that TH subtype specificity of Lat2 and its role in vivo are unclear, motivated us to gain insight into structure-function relationships of Lat2.

The central question of this project focuses on the understanding of the molecular mechanism of TH transport at the Lat2 transporter. Due to the missing detailed experimental structural information for all TH transmembrane transporters, we initially build homology models for Lat2 based on crystal structures of other transporter proteins comprising 12 transmembrane segments of high sequence similarity. This enables the analysis of structure-function-relationships, which help in an iterative procedure to identify residues responsible for recognition and transport of TH derivatives by site directed mutagenesis of Lat2.

Beside variants of Lat2 we also consider variants of the TH. Thus we ask, which of the TH derivatives are preferentially transported by Lat2 and which molecular and structural determinants (amino acids) of LAT2 are responsible as counterparts for the transport for TH. Apart considering T3 and T4  we focus our attention especially also on T2, since little is known about its role. Furthermore, the specificity patterns of the substrate will help us to study TH derivatives transported by Lat2 in vivo. In addition, we will generate a web-based platform for interactive data analyses of TH transporters and TH derivatives which will be shared with other groups of the SPP.

 

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Project Coordinator(s):

Dr. Anita Kinne
Leibniz Institut für Molekulare Pharmakologie (FMP)
Structural Bioinformatics and Protein Design
Robert-Rössle-Str. 10
13125 Berlin
Phone: +49 30 94793 388
Fax: +49 30 94793 109
kinne@fmp-berlin.de

Dr. Gerd Krause
Leibniz Institut für Molekulare Pharmakologie (FMP)
Structural Bioinformatics and Protein Design
Robert-Rössle-Str. 10
13125 Berlin
Phone: +49 30 94793 228
Fax: +49 30 94793 230
gkrause@fmp-berlin.de