Mutual adaptation of a membrane protein and its lipid bilayer during conformational changes

Abstract

The structural elucidation of membrane proteins continues to gather pace, but we know little about their molecular interactions with the lipid environment or how they interact with the surrounding bilayer. Here, with the aid of low-resolution X-ray crystallography, we present direct structural information on membrane interfaces as delineated by lipid phosphate groups surrounding the sarco(endo)plasmic reticulum Ca 2 + -ATPase (sERCA) in its phosphorylated and dephosphorylated Ca 2 + -free forms. The protein-lipid interactions are further analysed using molecular dynamics simulations. We find that sERCA adapts to membranes of different hydrophobic thicknesses by inducing local deformations in the lipid bilayers and by undergoing small rearrangements of the amino-acid side chains and helix tilts. These mutually adaptive interactions allow smooth transitions through large conformational changes associated with the transport cycle of sERCA, a strategy that may be of general nature for many membrane proteins.

Modulation of Plasma Membrane Ca2+-ATPase by Neutral Phospholipids

“…This result was similar for higher X PC , suggesting that the increase of t(EP) is related to the physical state of the micelles or bicelles and not to changes in the bilayer thickness. In agreement with these findings, Sonntag et al (15) suggested that a change in the bilayers hydrophobic thickness in SERCA may have a direct effect on the conformational change between the E 1 and E 2 states.…”

“…Although the detergent molecules would probably increase the membrane fluidity, it has been demonstrated that the thickness of a bilayer composed of C 12 E 8 and DOPC (in a ratio of 30:80 (i.e. an X PC of about 0.3)) remained nearly constant with respect to a pure phospholipid (15). Importantly, the protein structure was only slightly affected by the detergent environment, consistent with its functional integrity.…”

“…However, a more detailed analysis of this effect on the whole spectrum of phospholipid/detergent molar ratio is yet to be performed. Moreover, it has been shown for other P-type ATPases that the hydrophobic thickness of the surrounding bilayer exerts an effect over the enzyme activity (5,15,16). Because the hydrophobic thickness of the lipid bilayer is expected to match the hydrophobic thicknesses of the proteins inserted in that membrane (17), the use of phospholipids with different chain lengths in the micelle may shed light on the elucidation of the optimal conditions for measuring PMCA activity.…”

Structure and mechanism of ATP-dependent phospholipid transporters

“…Two speculative models on ABC-type flippases have been proposed, the "tilting model" and the "rotating helix model", that are however not exclusive [93,216]. In the tilting model, a variation of the alternating access model, the lipid enters the chamber of MsbA from the inner leaflet of the bilayer.…”

Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport

“…Critical lipid dependencies have also been established for P-type ATPases. The Ca 2þ -transporting P-type ATPase SERCA1a is unstable in the absence of lipids (64), requires an~30-Å -thick lipid bilayer for optimal function (65,66), and induces local deformations in the surrounding lipid bilayer (67). Likewise, the function of copper-transporting P-type ATPases is lipid dependent, since proteins solubilized in detergent are inactive in the absence of supplemented lipids (9,68,69).…”