The methionine-aromatic motif plays a unique role in stabilizing protein structure

Christopher C. Valley, Alessandro Cembran, Jason D. Perlmutter, Andrew K. Lewis, Nicholas P. Labello, Jiali Gao, Jonathan N. Sachs

Research output: Contribution to journalArticle

139 Scopus citations

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 Metaromatic 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.

Original languageEnglish (US)
Pages (from-to)34979-34991
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number42
DOIs
StatePublished - Oct 12 2012

Fingerprint Dive into the research topics of 'The methionine-aromatic motif plays a unique role in stabilizing protein structure'. Together they form a unique fingerprint.

  • Cite this