Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 42; pp. 17747 - 17750
• Main Authors: Oberai, Amit, Joh, Nathan H, Pettit, Frank K, Bowie, James U
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.10.2009; National Acad Sciences
• Subjects: Adenosine triphosphatases; Amino acids; Biological Sciences; Biophysical Phenomena; Cells; Databases, Protein; Evolution; Evolution, Molecular; Genetic mutation; Humans; Hydrophobic and Hydrophilic Interactions; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membranes; Models, Molecular; Mutation; P branes; P values; Polymorphism; Polymorphism, Single Nucleotide; Protein Folding; Protein Structure, Secondary; Proteins; Solubility; String theory; Surface areas
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906390106

The amino acid sequences of transmembrane regions of helical membrane proteins are highly constrained, diverging at slower rates than their extramembrane regions and than water-soluble proteins. Moreover, helical membrane proteins seem to fall into fewer families than water-soluble proteins. The reason for the differential restrictions on sequence remains unexplained. Here, we show that the evolution of transmembrane regions is slowed by a previously unrecognized structural constraint: Transmembrane regions bury more residues than extramembrane regions and soluble proteins. This fundamental feature of membrane protein structure is an important contributor to the differences in evolutionary rate and to an increased susceptibility of the transmembrane regions to disease-causing single-nucleotide polymorphisms.