1- Dept of Cell and Molecular Biology, Tehran University, Tehran, Iran 2- Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran , mtaghizadeh@alumni.ut.ac.ir 3- Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran
Abstract: (6508 Views)
Introduction: Recently, 6 crystallographic structures of the pharmacologically important human serotonin transporter protein (5-HTT) were reported. In the present survey, two of these crystallographic structures and two homology models were used to study the distribution of 5-HTT’s residues based on their position and orientation. The aim here was to understand the structural and functional roles of membrane helices better in transporters and the costs/benefits of using homology models in such studies.
Materials & methods: The membrane helical segments of 5-HTT were identified using a KD-hydropathy plot. The classification of membrane helical residues into 4 groups (Lipid-facing, Lumen-facing, Right and Left) was done using a novel method considering residue positions. Also two 3D structural models of 5-HTT were generated using MODELLER based on templates with 38% and 60% similarities.
Findings: Although the majority of hydrophobic residues in membrane helices were in the Lipid-facing cluster, a considerable percentage of them laid within the Lumen-facing cluster. In the Lipid-facing cluster, Ile, Leu, Val, Thr, Ala and Phe were the most frequent residues, respectively. Thus, their 3D positioning patterns were responsible for most of protein-lipid interactions and the functions of these interactions.
Discussion & conclusions: Judging by the correlation coefficients, Lipid-facing and Right clusters are the most similar. This suggests that helices may rotate during the outward-inward conformational switch of the transporters. Our model-crystal structure comparisons demonstrate that in the case of membrane transporters, using a template with 38% similarity, results in poor modeling of the membrane helices. These findings can help us understand the structure and function of membrane helices in transporter proteins better.
Shariat Panahi A, Taghizadeh M, Goliaei B, Madadkar Sobhani A. Clustering Membrane Helical Residues in the Human Serotonin Transporter. J. Ilam Uni. Med. Sci. 2017; 25 (3) :57-72 URL: http://sjimu.medilam.ac.ir/article-1-4084-en.html