MINIREVIEW PROLOGUE
Membrane Protein Structural Biology Minireview
Series*
William L.
Smith
,
R. Michael
Garavito, and
Shelagh
Ferguson-Miller
From the Department of Biochemistry and Molecular
Biology, Michigan State University, East Lansing, Michigan 48824
 |
ARTICLE |
It is estimated that one-third of all proteins
are integral membrane proteins, defined narrowly as proteins that
completely traverse the membrane bilayer. There also exists a smaller
but unknown number of monotopic membrane proteins, including
prostaglandin endoperoxide H synthases, that interdigitate into a
single leaflet of the lipid bilayer via a specific membrane binding
domain (1). Additionally, there are acylated and/or prenylated proteins
such as endothelial cell nitric oxide synthase (2) that depend on lipid
modifications for their binding to membranes or membrane subdomains
including lipid rafts (3) as well as proteins such as protein kinase C,
cytosolic, Ca2+-dependent phospholipase
A2 (4), and protein kinase B that undergo dissociable
interactions with membranes via C1 and/or C2 or pleckstrin homology or
FYVE domains in the context of cellular signaling.
Despite the fact that there now are over 14,000 independent
protein structures in the Protein Data Bank only about two dozen of these are membrane proteins.1
This reflects the difficulties of
performing structural studies on proteins of this type. There appear to
be two major classes of integral membrane proteins, the 
-helical
transmembrane proteins broadly distributed in cellular and organellar
membranes and the 
-barrel-containing porins found in the outer
membranes of Gram-negative bacteria and mitochondrial and chloroplast
membranes. This four-part minireview series focuses primarily on the
-helical and -barrel proteins and intracellular proteins that can
associate reversibly with membranes via C1 and C2 domains. Excellent
minireviews on the related topics of lipids as protein chaperones (5),
the structures of bacterial ion channels (6), and pleckstrin homology and FYVE domains (7) have also appeared recently.
The first minireview of this series entitled "How
Membranes Shape Protein Structure" by Stephen H. White, Alexey S. Ladokhin, Sajith Jayasinghe, and Kalina Hristova focuses on the
structure and folding of -helical transmembrane domain-containing
proteins. Two important concepts are developed. The first is that of
the lipid bilayer being comprised of two chemically distinct regions of
different hydrophobicities, a relatively polar membrane interface and a
relatively nonpolar hydrocarbon core. Interestingly and importantly,
these two membrane regions are of approximately equal thermal thickness
per monolayer. The membrane interface is the region where much of
membrane protein folding takes place. The second important concept is
that of the overriding thermodynamic importance of the peptide bond and
of the need to form hydrogen bonds between peptide bonds prior to
insertion of -helical proteins into the membrane. This latter
concept is discussed in the context of a four-step model for
-helical membrane protein assembly that involves partitioning of the
unfolded protein into the membrane interface, folding to an -helical
structure, insertion of the -helix into the bilayer, and finally and
as necessary, assembly of individual helices into bundles.
The second minireview of the series entitled "Structure and Assembly
of -Barrel Membrane Proteins" by Lukas K. Tamm, Ashish Arora, and
Jörg H. Kleinschmidt focuses on the other major class of integral
membrane proteins. In this minireview Tamm et al. describe
the various known types of -barrel proteins that contain 8, 12, 16, and 18 anti-parallel strands assembled in different quaternary
structures. Again, this review highlights and reinforces the importance
of forming hydrogen-bonded secondary structures in order for any
protein to be inserted into a bilayer membrane. The authors also
summarize evidence from elegant experiments with OmpA, an
eight-stranded -barrel protein, for a four-step model for the
folding and insertion of -barrel proteins into membranes. This model
is similar to that for assembly of -helical proteins except that a
significant part of the folding, following H-bond formation, occurs
within the membrane as the -barrel protein moves from an H-bonded
but partially folded "molten disc" form to a mature "native" protein.
The third minireview entitled "Detergents as Tools in
Membrane Biochemistry" by R. Michael Garavito and Shelagh
Ferguson-Miller describes the physical and chemical properties of
synthetic detergents used in solubilizing, purifying, and crystallizing
membrane proteins. The authors emphasize the importance of
understanding the phase behaviors of detergents when considering these
reagents as preparative tools for obtaining purified membrane proteins
for functional and structural studies. For example, they provide a
current view of the dynamic structures of micelles and how these are
influenced by salts, other polar solutes and proteins, as well as
how detergents in various different physical states interact with and
influence membrane protein structures. The authors also highlight
examples of the specific binding of membrane lipids to proteins. This
important concept in membrane protein structural biology has become
apparent from recent high-resolution x-ray crystallographic studies of bacteriorhodopsin and cytochrome c oxidase. Specifically
bound lipids may well be the rule rather than the exception, and in many instances it may be advantageous to retain these bound lipids in
the presence of solubilizing detergents.
The final minireview of this series by Wonhwa Cho is
entitled "Membrane Targeting by C1 and C2 Domains." C1 and C2
domains were first discovered in protein kinase C. The C1 domain is
known to bind 1,2-diacylglycerol that is produced in the membrane as a
product of the action of hormone-activated phospholipase C on phosphatidylinositol 4,5-bisphosphate. The C2 domain is a structural motif that has now been identified in a number of proteins including protein kinase C, cytosolic phospholipase A2, and
synaptotagmins. Different C2 domains can bind either two or three
divalent calcium ions reversibly. Ca2+ binds to C2 domains
when there are hormone-induced increases in the concentration of
intracellular Ca2+. Once Ca2+ becomes bound to
a C2 domain, this domain binds to intracellular membranes. For example,
protein kinase C binds to the plasma membrane and cytosolic
phospholipase A2 binds to the endoplasmic reticulum and
nuclear envelope. Cho describes the properties of C1 and C2 domains and
their modes of association with membranes.
The authors and editors hope that this minireview series on membrane
protein structural biology will enable researchers in the biological
and chemical sciences to appreciate and explore further this novel
group of proteins.
| |
FOOTNOTES |
*
This minireview will be reprinted
in the 2001 Minireview Compendium, which
will be available in December, 2001.
To whom correspondence should be addressed: Biochemistry Bldg.,
Rm. 513, Dept. of Biochemistry and Molecular Biology, Michigan State
University, East Lansing, MI 48824. Tel.: 517-353-0804; Fax:
517-353-9334; E-mail: smithww@msu.edu.
Published, JBC Papers in Press, June 29, 2001, DOI 10.1074/jbc.R100044200
1
blanco.biomol.uci.edu/Membrane_Proteins_xtal.html.
| |
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Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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