Foreword
The Emergence of Membrane Protein Biochemistry
Biochemistry aims to reveal the workings of biological molecules using the concepts of chemistry.
While chemical conceptualizations have successfully revealed the operations of many soluble proteins
and machines as large and complex as ribosomes, advances in such understanding have only recently
begun to emerge for many of the macromolecular components of membranes. The very slow progress
toward biochemical insights into membrane proteins and complexes can be understood as a methodological challenge, which is explored by Jean-Luc Popot in this excellent book Membrane Proteins in
Aqueous Solutions: From Detergents to Amphipols. The challenge, which has only recently been
overcome for most proteins, is to enable biochemical studies of structure and function by creating
relatively stable, homogeneous preparations of proteins and complexes in aqueous solution, where
they can be studied using the tools of biochemistry.
In the early 1970s, membrane protein biochemistry was a mystery. The basic lipid bilayer
structure of membranes had been agreed upon, and there was also agreement that proteins must
mediate membrane functions. Physiologists and molecular biologists had found that channels,
transporters, permeases, and other functional elements mediate the translocation of ions, the conduction of nerve impulses, the transduction of energy, and many other key processes of living systems, but
the chemistry of these functions was dramatically limited by the paucity of structural information. To
illustrate the state of affairs, I note the idea of membrane protein structure shown in Fig. 1.
At the same time, a rapidly growing number of protein structural models had been established in
chemical detail, and the biochemistry of a number of enzyme functions was understood from a
chemical perspective that combined structural and functional data. Why did such a disparity exist
between rapid advances in protein chemistry up to 1990 and the glacial pace of understanding
membrane proteins?
The approaches that had been used were largely limited by the detergent strategies used to
remove proteins from the lipid bilayer environments of membranes, and only a subset of the membrane
menagerie could be examined as stable entities. Further, only a small subset of the menagerie could be
crystallized for structural study, and only a still smaller subset allowed the resolution needed for the
creation of chemically detailed models.
Two significant paths are now expanding our view: new methods of creating stable structures
outside of the membrane context and a new method for examining their structures. The new structural
method is single-particle electron cryomicroscopy (cryo-EM), and the new methods of preparation
include nanodiscs and amphipols. A remarkable example of how such approaches combine is in the
recent structure of a ligand-gated ion channel, TRPV1, stabilized in solution by an amphipol (Liao
et al. 2013). This structure alone leapfrogs decades of work, mostly based on the “divide and conquer”
vii
The Emergence of Membrane Protein Biochemistry
Biochemistry aims to reveal the workings of biological molecules using the concepts of chemistry.
While chemical conceptualizations have successfully revealed the operations of many soluble proteins
and machines as large and complex as ribosomes, advances in such understanding have only recently
begun to emerge for many of the macromolecular components of membranes. The very slow progress
toward biochemical insights into membrane proteins and complexes can be understood as a methodological challenge, which is explored by Jean-Luc Popot in this excellent book Membrane Proteins in
Aqueous Solutions: From Detergents to Amphipols. The challenge, which has only recently been
overcome for most proteins, is to enable biochemical studies of structure and function by creating
relatively stable, homogeneous preparations of proteins and complexes in aqueous solution, where
they can be studied using the tools of biochemistry.
In the early 1970s, membrane protein biochemistry was a mystery. The basic lipid bilayer
structure of membranes had been agreed upon, and there was also agreement that proteins must
mediate membrane functions. Physiologists and molecular biologists had found that channels,
transporters, permeases, and other functional elements mediate the translocation of ions, the conduction of nerve impulses, the transduction of energy, and many other key processes of living systems, but
the chemistry of these functions was dramatically limited by the paucity of structural information. To
illustrate the state of affairs, I note the idea of membrane protein structure shown in Fig. 1.
At the same time, a rapidly growing number of protein structural models had been established in
chemical detail, and the biochemistry of a number of enzyme functions was understood from a
chemical perspective that combined structural and functional data. Why did such a disparity exist
between rapid advances in protein chemistry up to 1990 and the glacial pace of understanding
membrane proteins?
The approaches that had been used were largely limited by the detergent strategies used to
remove proteins from the lipid bilayer environments of membranes, and only a subset of the membrane
menagerie could be examined as stable entities. Further, only a small subset of the menagerie could be
crystallized for structural study, and only a still smaller subset allowed the resolution needed for the
creation of chemically detailed models.
Two significant paths are now expanding our view: new methods of creating stable structures
outside of the membrane context and a new method for examining their structures. The new structural
method is single-particle electron cryomicroscopy (cryo-EM), and the new methods of preparation
include nanodiscs and amphipols. A remarkable example of how such approaches combine is in the
recent structure of a ligand-gated ion channel, TRPV1, stabilized in solution by an amphipol (Liao
et al. 2013). This structure alone leapfrogs decades of work, mostly based on the “divide and conquer”
vii