title: The methionine-aromatic motif plays a unique role in stabilizing protein structure.
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.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Valley
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cembran
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Perlmutter
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Lewis
authors.affiliation: Department of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Labello
authors.affiliation: Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Jiali
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455. Electronic address: jnsachs@umn.edu.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
mesh_terms: D020816:Amino Acid Motifs; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008233:Lymphotoxin-alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008233:Lymphotoxin-alpha; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C506236:Tnfrsf1a protein, mouse; D008715:Methionine