title: General and specific lipid-protein interactions in Na,K-ATPase.
abstract: The molecular activity of Na,K-ATPase and other P2 ATPases like Ca(2+)-ATPase is influenced by the lipid environment via both general (physical) and specific (chemical) interactions. Whereas the general effects of bilayer structure on membrane protein function are fairly well described and understood, the importance of the specific interactions has only been realized within the last decade due particularly to the growing field of membrane protein crystallization, which has shed new light on the molecular details of specific lipid-protein interactions. It is a remarkable observation that specific lipid-protein interactions seem to be evolutionarily conserved, and conformations of specifically bound lipids at the lipid-protein surface within the membrane are similar in crystal structures determined with different techniques and sources of the protein, despite the rather weak lipid-protein interaction energy. Studies of purified detergent-soluble recombinant αβ or αβFXYD Na,K-ATPase complexes reveal three separate functional effects of phospholipids and cholesterol with characteristic structural selectivity. The observations suggest that these three effects are exerted at separate binding sites for phophatidylserine/cholesterol (stabilizing), polyunsaturated phosphatidylethanolamine (stimulatory), and saturated PC or sphingomyelin/cholesterol (inhibitory), which may be located within three lipid-binding pockets identified in recent crystal structures of Na,K-ATPase. The findings point to a central role of direct and specific interactions of different phospholipids and cholesterol in determining both stability and molecular activity of Na,K-ATPase and possible implications for physiological regulation by membrane lipid composition. This article is part of a special issue titled "Lipid-Protein Interactions."
authors: Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark. Electronic address: fc@biomed.au.dk.
authors: F
authors: F
authors: Cornelius
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: M
authors: M
authors: Habeck
authors: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors: R
authors: R
authors: Kanai
authors: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors: C
authors: C
authors: Toyoshima
authors: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: S J D
authors: SJ
authors: Karlish
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008563:Membrane Lipids; D008565:Membrane Proteins; D010743:Phospholipids; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Cholesterol; Na,K-ATPase phospholipid; Recombinant Na,K-ATPase complexes; Reconstitution; Specific lipid–protein interactions; X-ray crystal structure