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Published online before print March 5, 2008

0031-6997/08/6001-43-78$7.00
Pharmacol Rev 60:43-78, 2008

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Vertebrate Membrane Proteins: Structure, Function, and Insights from Biophysical Approaches

Daniel J. Müller, Nan Wu and Krzysztof Palczewski

Biotechnology Center, University of Technology, Dresden, Germany (D.J.M.); and Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (N.W., K.P.)

Abstract
I. Introduction
II. Overview of Vertebrate Membranes
    A. Properties of Plasma and Endoplasmic Reticulum Membranes
    B. Membrane Proteins
III. Interactions of Proteins with Membranes
    A. Dynamic Nature of Membrane Proteins
    B. Interactions of Membrane Proteins with Phospholipids
    C. Sequestration of Charges within Membrane Proteins
    D. Forces Driving the Assembly of Membrane Proteins
    E. Modulation of Membrane Protein Function by Lipids
    F. Energy Landscape Determines Reaction Pathways and Kinetics (Dynamics) of Membrane Proteins
IV. Imaging Membrane Proteins
    A. Membrane Proteins in Two-Dimensional Crystals
    B. Membrane Proteins Observed by Atomic Force Microscopy
        1. Observing Diffusion and Assembly of Membrane Proteins.
        2. Imaging Native Membranes of Vertebrates.
    C. Changes in the Structure of Membrane Proteins Observed by Atomic Force Microscopy
    D. Membrane Proteins Observed by Near-Field Scanning Optical Microscopy and Single-Molecule Fluorescence Microscopy
V. Detecting Intramolecular Interactions of Membrane Proteins by Single-Molecule Force Spectroscopy
    A. Description of Single-Molecule Force Spectroscopy
    B. Direct Detection and Localization of Interactions
    C. Unfolding and Folding Pathways
    D. Mapping Intramolecular Interactions of a G Protein-Coupled Receptor
    E. Detecting How Intramolecular Interactions of a G Protein-Coupled Receptor Change within a Physiologically Relevant Range
    F. Detecting and Locating Ligand-Binding That Modulates the Functional State of Single-Membrane Proteins
    G. Energy Landscape of Membrane Protein Unfolding and Thermodynamic Considerations
    H. Changes in Intramolecular Interactions Alter the Energy Landscape of Membrane Proteins
    I. Mutations Change the Energy Landscape and Reaction Pathways of Membrane Proteins
VI. Pharmacological Challenges and Opportunities Involving Membrane Proteins
VII. Unresolved Issues and Concluding Remarks
Membrane proteins are key targets for pharmacological intervention because they are vital for cellular function. Here, we analyze recent progress made in the understanding of the structure and function of membrane proteins with a focus on rhodopsin and development of atomic force microscopy techniques to study biological membranes. Membrane proteins are compartmentalized to carry out extra- and intracellular processes. Biological membranes are densely populated with membrane proteins that occupy approximately 50% of their volume. In most cases membranes contain lipid rafts, protein patches, or paracrystalline formations that lack the higher-order symmetry that would allow them to be characterized by diffraction methods. Despite many technical difficulties, several crystal structures of membrane proteins that illustrate their internal structural organization have been determined. Moreover, high-resolution atomic force microscopy, near-field scanning optical microscopy, and other lower resolution techniques have been used to investigate these structures. Single-molecule force spectroscopy tracks interactions that stabilize membrane proteins and those that switch their functional state; this spectroscopy can be applied to locate a ligand-binding site. Recent development of this technique also reveals the energy landscape of a membrane protein, defining its folding, reaction pathways, and kinetics. Future development and application of novel approaches during the coming years should provide even greater insights to the understanding of biological membrane organization and function.

Address correspondence to: Dr. Krzysztof Palczewski, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, Ohio 44106-4965. E-mail: kxp65{at}case.edu




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