The effect of iodide and chloride on transthyretin structure and stability

Hörnberg, Andreas,1972-Umeå universitet,Umeå centrum för molekylär patogenes (UCMP) (författare)

Transthyretin amyloid formation occurs through a process of tetramer destabilization and partial unfolding. Small molecules, including the natural ligand thyroxine, stabilize the tetrameric form of the protein, and serve as inhibitors of amyloid formation. Crucial for TTR's ligand-binding properties are its three halogen-binding sites situated at the hormone-binding channel. In this study, we have performed a structural characterization of the binding of two halides, iodide and chloride, to TTR. Chlorides are known to shield charge repulsions at the tetrameric interface of TTR, which improve tetramer stability of the protein. Our study shows that iodides, like chlorides, provide tetramer stabilization in a concentration-dependent manner and at concentrations approximately 15-fold below that of chlorides. To elucidate binding sites of the halides, we took advantage of the anomalous scattering of iodide and used the single-wavelength anomalous dispersion (SAD) method to solve the iodide-bound TTR structure at 1.8 A resolution. The structure of chloride-bound TTR was determined at 1.9 A resolution using difference Fourier techniques. The refined structures showed iodides and chlorides bound at two of the three halogen-binding sites located at the hydrophobic channel. These sites therefore also function as halide-binding sites.

Wikström Hultdin, UlrikaUmeå universitet,Kemiska institutionen(Swepub:umu)ulawim01 (författare)
Olofsson, AndersUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)anol0042 (författare)
Sauer-Eriksson, ElisabethUmeå universitet,Kemiska institutionen(Swepub:umu)elsa0002 (författare)
Umeå universitetUmeå centrum för molekylär patogenes (UCMP) (creator_code:org_t)

Ingår i:Biochemistry: American Chemical Society (ACS)44:26, s. 9290-92990006-29601520-4995

Av författaren/redakt...: Hörnberg, Andrea ...; Wikström Hultdin ...; Olofsson, Anders; Sauer-Eriksson, ...

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