1. The methionine-aromatic motif plays a unique role in stabilizing protein structure.
- Author
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Valley CC, Cembran A, Perlmutter JD, Lewis AK, Labello NP, Gao J, and Sachs JN
- Subjects
- Amino Acid Motifs, HEK293 Cells, Humans, Jurkat Cells, Lymphotoxin-alpha genetics, Lymphotoxin-alpha metabolism, Methionine genetics, Methionine metabolism, Mutation, Protein Stability, Protein Structure, Quaternary, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, TNF-Related Apoptosis-Inducing Ligand genetics, TNF-Related Apoptosis-Inducing Ligand metabolism, Lymphotoxin-alpha chemistry, Methionine chemistry, Receptors, TNF-Related Apoptosis-Inducing Ligand chemistry, Receptors, Tumor Necrosis Factor, Type I chemistry, TNF-Related Apoptosis-Inducing Ligand chemistry
- Abstract
Of the 20 amino acids, the precise function of methionine (Met) remains among the least well understood. To establish a determining characteristic of methionine that fundamentally differentiates it from purely hydrophobic residues, we have used in vitro cellular experiments, molecular simulations, quantum calculations, and a bioinformatics screen of the Protein Data Bank. We show that approximately one-third of all known protein structures contain an energetically stabilizing Met-aromatic motif and, remarkably, that greater than 10,000 structures contain this motif more than 10 times. Critically, we show that as compared with a purely hydrophobic interaction, the Met-aromatic motif yields an additional stabilization of 1-1.5 kcal/mol. To highlight its importance and to dissect the energetic underpinnings of this motif, we have studied two clinically relevant TNF ligand-receptor complexes, namely TRAIL-DR5 and LTα-TNFR1. In both cases, we show that the motif is necessary for high affinity ligand binding as well as function. Additionally, we highlight previously overlooked instances of the motif in several disease-related Met mutations. Our results strongly suggest that the Met-aromatic motif should be exploited in the rational design of therapeutics targeting a range of proteins.
- Published
- 2012
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