Why are polar residues within the membrane core evolutionary conserved?

Abstract

Here, we present a study of polar residues within the membrane core of alpha‐helical membrane proteins. As expected, polar residues are less frequent in the membrane than expected. Further, most of these residues are buried within the interior of the protein and are only rarely exposed to lipids. However, the polar groups often border internal water filled cavities, even if the rest of the sidechain is buried. A survey of their functional roles in known structures showed that the polar residues are often directly involved in binding of small compounds, especially in channels and transporters, but other functions including proton transfer, catalysis, and selectivity have also been attributed to these proteins. Among the polar residues histidines often interact with prosthetic groups in photosynthetic‐ and oxidoreductase‐related proteins, whereas prolines often are required for conformational changes of the proteins. Indeed, the polar residues in the membrane core are more conserved than other residues in the core, as well as more conserved than polar residues outside the membrane. The reason is twofold; they are often (i) buried in the interior of the protein and (ii) directly involved in the function of the proteins. Finally, a method to identify which polar residues are present within the membrane core directly from protein sequences was developed. Applying the method to the set of all human membrane proteins the prediction indicates that polar residues were most frequent among active transporter proteins and GPCRs, whereas infrequent in families with few transmembrane regions, such as non‐GPCR receptors. Proteins 2010. © 2010 Wiley‐Liss, Inc.

Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations

“…Polar residues in membrane proteins are under evolutionary pressure for conservation and hence maintain common functions with essential roles in stability, activation, and interhelical association through the formation of hydrogen bonds (8). Based on our GLP-1R model, two main hydrogen-bond networks involving conserved polar side chains located between TMs 2, 3, 6, and 7 and waters are evident.…”

“…Therefore, most polar residues in TM helices are buried within the interior of the protein, often lining internal water-filled cavities and forming hydrogen-bond interactions with buried water molecules and other polar residues (7,8). Consequently, they play essential roles in the function of α-helical membrane proteins by mediating and stabilizing their helical interactions (9), in addition to playing key roles in transmission of signals across membranes through forming interactions with ligands and establishing interaction networks required for protein conformational changes (10).…”

Type IV pilins regulate their own expression via direct intramembrane interactions with the sensor kinase PilS

“…Thus, multiple contacts are important for the pilin-PilS interaction. Rare charged residues in TM segments are typically buried within multi-TM proteins or involved in protein-protein interactions (48,49). PilA E5K or PilS R24E substitutions disrupted PilA-PilS interactions and dysregulated PilA expression, but the PilA E5K and PilS R24E charged-swapped pair failed to interact (Fig.…”

Structure-based statistical analysis of transmembrane helices

“…These residues constitute only 8.2 % of the residues within TM helices compared to 30.9 % in water-soluble helices. Despite their lower presence, polar residues are evolutionary conserved in TM proteins, which has been partially explained by their tendency to be buried in the protein interior and also in many cases due to their direct involvement in the function of the protein (Illergård et al, 2011).…”