Asn441 plays a key role in folding and function of the Na+/I− symporter (NIS)

• Autores: Li, Wenjing; Nicola, Juan Pablo; Amzel, L. Mario; Carrasco, Nancy
• Año de publicación: 2013
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Na+/I- Symporter; Iodide Transport Defect; Homology Model; Helix Capping
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

The Na+/I− symporter (NIS) is a plasma membrane glycoprotein that mediates active I− transport in the thyroid, the first step in the biosynthesis of the iodine-containing thyroid hormones T3 and T4. Several NIS mutants have been identified as a cause of congenital I− transport defect (ITD), and their investigation has yielded valuable mechanistic information on NIS. Here we report a thorough characterization of the ITD-causing NIS mutation in which the sixth intracellular loop residues 439–443 are missing. This mutant protein was intracellularly retained, incompletely glycosylated, and intrinsically inactive. Engineering 5 Ala at positions 439–443 partially recovered cell surface targeting and activity (∼15%). Strikingly, NIS with the sequence 439-AANAA-443, in which Asn was restored at position 441, was targeted to the plasma membrane and exhibited ∼95% the transport activity of WT NIS. Based on our NIS homology model, we propose that the side chain of N441, a residue conserved throughout most of the SLC5 family, interacts with the main chain amino group of G444, capping the α-helix of transmembrane segment XII and thus stabilizing the structure of the molecule. Our data provide insight into a critical interhelical interaction required for NIS folding and activity.—Li, W., Nicola, J. P., Amzel, L. M., Carrasco, N. Asn441 plays a key role in folding and function of the Na+/I− symporter (NIS).
Fil: Li, Wenjing. Albert Einstein College of Medicine; Estados Unidos
Fil: Nicola, Juan Pablo. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Amzel, L. Mario. University Johns Hopkins; Estados Unidos
Fil: Carrasco, Nancy. University of Yale; Estados Unidos