The evolution of transmembrane helix kinks and the structural diversity of G protein-coupled receptors

Abstract

One of the hallmarks of membrane protein structure is the high frequency of transmembrane helix kinks, which commonly occur at proline residues. Because the proline side chain usually precludes normal helix geometry, it is reasonable to expect that proline residues generate these kinks. We observe, however, that the three prolines in bacteriorhodopsin transmembrane helices can be changed to alanine with little structural consequences. This finding leads to a conundrum: if proline is not required for helix bending, why are prolines commonly present at bends in transmembrane helices? We propose an evolutionary hypothesis in which a mutation to proline initially induces the kink. The resulting packing defects are later repaired by further mutation, thereby locking the kink in the structure. Thus, most prolines in extant proteins can be removed without major structural consequences. We further propose that nonproline kinks are places where vestigial prolines were later removed during evolution. Consistent with this hypothesis, at 14 of 17 nonproline kinks in membrane proteins of known structure, we find prolines in homologous sequences. Our analysis allows us to predict kink positions with >90% reliability. Kink prediction indicates that different G protein-coupled receptor proteins have different kink patterns and therefore different structures.

Point Mutations in Membrane Proteins Reshape Energy Landscape and Populate Different Unfolding Pathways

“…A number of proline residues at transmembrane α-helix kinks were also replaced by alanine. 16 P50A had no effect on stability, whereas P91A and P186Awere found to be somewhat destabilizing with associated changes in ΔΔG u of −1.3±0.3 and −0.9±0.1 kcal/mol, respectively. None of the proline substitutions altered the structure of the proteins beyond local adjustments near the kinks.…”

“…None of the proline substitutions altered the structure of the proteins beyond local adjustments near the kinks. 15,16 Figure 1 shows the positions of the five mutations, P50A, M56A, Y57A in transmembrane α-helix B, P91A in α-helix C, and P186A in α-helix F of BR.…”

Biomimetic Conducting Polymers: Synthesis, Materials, Properties, Functions, and Devices

“…Most of the biological reactions involving proteins, enzymes, nucleic acids, or ionic channels also include conformational 100 and folding/unfolding processes [101][102][103] responding, as CPs do, to different external stimuli. 104 Biochemical books include from a long time ago allosteric effects that "arises when the reaction of ligands with one site of any polyvalent molecule affects the reaction of ligands at one or more other sites as a result of conformational changes."…”

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

“…3,[128][129][130] This is especially important due to the large number of important pharmacological targets within the large GPCR family. [131][132][133][134][135][136][137][138][139][140][141][142] In our simulation results, the nature of the coupling between a local conformational change and a large-scale helix and loop change may be similar across the GPCR family. This would imply that the effect of ligand binding to a GPCR is tightly regulated by a coupled set of energetic interactions, in a similar manner to that found within the retinal-rhodopsin system.…”