General Features of Membrane Protein Structures

Presently, about 160 coordinate files of membrane protein structures are accessible in the PDB. Among them, roughly 80 are unique proteins (see http://blan-co.biomol.uci.edu/Membrane_Proteins_xtal.html). Despite a significant increase in the last couple of years, the growth rate since 1986 is still not comparable to the early days of soluble protein structure determination (White 2004). The large majority of membrane proteins in the PDB span over both sides of the membrane, with a few exceptions (prostaglandin synthase, cyclooxigenase and squalene-ho-pene cyclase) which are monotopic. A third of the proteins are P-barrel proteins found in bacterial outer membranes. The first to be structurally characterized were porins, which are very stable and were very useful in the early development of membrane protein crystallization. Most of them are involved in transport processes and their structures contributed to the understanding of the mechanisms. However, there are still open questions. The transport of ferrichrome through FhuA (or FepA or FecA) still remains unclear; although a putative plug was identified in the structure, the access control through the plug mechanism needs additional evidence (Buchanan et al. 1999; Ferguson et al. 1998; Locher et al. 1998). TolC is a trimer that forms a single barrel, each monomer contributing with four strands. It is part of a complex machinery that drives the transport of small molecules between the cytosol and the exterior; the ensemble is still to be deciphered. Except in bacterial outer membranes, all other proteins are constituted by transmembrane helices. Proteins that are anchored in the membrane through a single transmembrane helix are clearly underrepresented in the PDB (except for monoamide oxidase and fatty acid amide hydrolase). Because the catalytic site is located in a large extramembrane domain, structural studies are undertaken after cleaving the transmembrane helix. However, this helix is often implicated in dimerization and therefore plays a crucial role in signaling. Solid state NMR is probably the best experimental approach to understand the dimerization process of such helices. The number of transmembrane helices in all the other integral membrane proteins present in the PDB is at least six or seven in the quartenary structures.

Figure 3.6 represents a sample of structures from the PDB, highlighting a variety of topologies. Some proteins consist as several subunits (11 subunits for the bovine heart cytochrome bcl complex, Fig. 3.6a). Others, such as ion channels, function as oligomers and the structures were determined in the oligomeric form (Figs. 3.6b, c and e). Whereas for a few of them the crystal structure is monomeric, they were shown to function in an oligomeric state in vivo (mitochondrial ADP/ ATP carrier, PDB code lokc). It is also interesting to note the existence of pseudo-symmetries either present in the structure (lactose permease, Fig. 3.6d) or resulting from multiple gene duplication (ADP/ATP carrier). Figure 3.6 also shows that transmembrane helices are more or less tilted with respect to the membrane, and that they can be straight or kinked. In some cases, helices can even span only over

CHAPTER 3: X-ray and Neutron Diffraction Approaches

Fig. 3.6. Examples of membrane protein structures. The transmembrane helices of all the proteins are aligned. It highlights the different tilt angles that these helices can adopt. Each colour represents a different subunit. The figure illustrates several membrane protein topologies (differences in size, in the number of transmembrane helices, in the number of subunits and in the size of the extramembrane domains), (a) Bovine bcl complex (11 subunits), PDB code: Ibgy. (b) One monomer of the glycerol facilitator (tetrameric structure), PDB code: 1fx8. (c) Inward rectifier potassium channel, PDB code: 1p7b. (d) Lactose permease, PDB code: 1pv7. (e) Monomer of bacteriorhodopsin (trimeric structure), PDB code: 1 qhj. (f) Preprotein translo-case SecY, PDB code: Irhz. The figure was prepared with the program PyMOL

half the membrane (aquaporins, Fig. 3.6b). As a result the global topology is more compact (bacterial rhodopsins, Fig. 3.6e), or forms large cavities (ADP/ATP carrier, Fig. 3.7).

Fig. 3.7. Examples of cardiolipins in membrane protein structures. The surfaces of the proteins are depicted in blue and the cardiolipins as ball and sticks, (a) ADP/ATP carrier, PDB code: lokc. (b) The photosynthetic reaction centre from R. sphaeroides, PDB code: Iqov. The figure was drawn with the program PyMOL

Fig. 3.7. Examples of cardiolipins in membrane protein structures. The surfaces of the proteins are depicted in blue and the cardiolipins as ball and sticks, (a) ADP/ATP carrier, PDB code: lokc. (b) The photosynthetic reaction centre from R. sphaeroides, PDB code: Iqov. The figure was drawn with the program PyMOL

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