OR34-3 Specific pathogenic mutations modulate monocarboxylate transporter 8 oligomerization

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR34-Molecular Mechanisms in Thyroid Hormone Action & Cancer
Basic/Translational
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:45 AM
Room 103 (Moscone Center)
Jana Fischer*, Gunnar Kleinau, Annette Grüters-Kieslich, Heiko Krude and Heike Biebermann
Charité - Universitätsmedizin Berlin, Berlin, Germany
The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS) and transports iodothyronines. Mutations in MCT8 are associated with severe X-linked psychomotor retardation and increased levels of hormone T3. It was previously reported that MCT8 is organized at the membrane as homo-oligomer, but details concerning functional or structural properties characterizing such complexed MCT8 were unknown so far. To obtain more detailed structural and functional insights into MCT8 oligomer formation we here investigated known naturally occurring (pathogenic) MCT8 variants concerning their capacities to form higher order complexes.

For 14 different MCT8-mutants we performed a Sandwich ELISA approach to study dimerization in comparison to wild type. It was assumed that potentially variations of MCT8 that affect amino acid side-chains oriented to the protein surface might interrupt putative MCT8-MCT8 interface contacts. Surprisingly, we found that exclusively mutations at five residues located directly inside the central transport channel cavity lead to a decrease of MCT8 oligomerization (dimer-separation). In contrast, only mutations (insertion, deletion, substitution) at the membrane spanning helix 2 cause enhanced dimerization capacities and a shift towards higher order complexes.

In conclusion, we here provide first structural information related to MCT8 oligomerization and conclude a causality between oligomerization, transport-mechanisms and particular structural features. These results might be helpful for a closer understanding of T3-transport and also related dysfunctionalities, which might be also important for other members of the MFS.

Nothing to Disclose: JF, GK, AG, HK, HB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm