Helix, transmembrane

Alpha helices that cross membranes are in a hydrophobic environment. Therefore, most of their side chains are hydrophobic. Long regions of hydrophobic residues in the amino acid sequence of a protein that is membrane-bound can therefore be predicted with a high degree of confidence to be transmembrane helices, as will be discussed in Chapter 12. 

Figure 12.3 Two-dimensional crystals of the protein bacteriorhodopsin were used to pioneer three-dimensional high-resolution structure determination from electron micrographs. An electron density map to 7 A resolution (a) was obtained and interpreted in terms of seven transmembrane helices (b).

Figure 12.S Schematic diagram of the bacteriorhodopsin molecule illustrating the relation between the proton channel and bound retinal in its tram form. A to E are the seven transmembrane helices. Retinal is covalently bound to a lysine residue. The relative positions of two Asp residues, which are important for proton transfer, are also shown. (Adapted from R. Henderson et al.,...

The polypeptide chain of the bacterial channel comprises 158 residues folded into two transmembrane helices, a pore helix and a cytoplasmic tail of 33 residues that was removed before crystallization. Four subunits... 

Figure 12.9 Schematic diagram of the stmc-ture of a potassium channel viewed perpendicular to the plane of the membrane. The molecule is tetrameric with a hole in the middle that forms the ion pore (purple). Each subunit forms two transmembrane helices, the inner and the outer helix. The pore heJix and loop regions build up the ion pore in combination with the inner helix. (Adapted from S.A. Doyle et al., Science 280 69-77, 1998.)...

The C-terminal transmembrane helix, the inner helix, faces the central pore while the N-terminal helix, the outer helix, faces the lipid membrane. The four inner helices of the molecule are tilted and kinked so that the subunits open like petals of a flower towards the outside of the cell (Figure 12.10). The open petals house the region of the polypeptide chain between the two transmembrane helices. This segment of about 30 residues contains an additional helix, the pore helix, and loop regions which form the outer part of the ion channel. One of these loop regions with its counterparts from the three other subunits forms the narrow selectivity filter that is responsible for ion selectivity. The central and inner parts of the ion channel are lined by residues from the four inner helices. 

The structurally similar L and M subunits are related by a pseudo-twofold symmetry axis through the core, between the helices of the four-helix bundle motif. The photosynthetic pigments are bound to these subunits, most of them to the transmembrane helices, and they are also related by the same twofold symmetry axis (Figure 12.15). The pigments are arranged so that they form two possible pathways for electron transfer across the membrane, one on each side of the symmetry axis. 

This pair of chlorophyll molecules, which as we shall see accepts photons and thereby excites electrons, is close to the membrane surface on the periplasmic side. At the other side of the membrane the symmetry axis passes through the Fe atom. The remaining pigments are symmetrically arranged on each side of the symmetry axis (Figure 12.15). Two bacteriochlorophyll molecules, the accessory chlorophylls, make hydrophobic contacts with the special pair of chlorophylls on one side and with the pheophytin molecules on the other side. Both the accessory chlorophyll molecules and the pheophytin molecules are bound between transmembrane helices from both subunits in pockets lined by hydrophobic residues from the transmembrane helices (Figure 12.16). 

Figure 12.16 View of the reaction center perpendicular to the membrane illustrating that the pigments are bound between the transmembrane helices. The five transmembrane-spanning a helices of the L (yellow) and the M (red) subunits are shown as well as the chlorophyll (green) and pheophytin (blue) molecules.

Figure 12.17 Computer-generated diagram of the stmcture of light-harvesting complex LH2 from Rhodopseudomonas acidophila. Nine a chains (gray) and nine p chains Bight blue) form two rings of transmembrane helices between which are bound nine carotenoids (yellow) and 27 bacteriochlorophyll molecules (red, green and dark blue). (Courtesy of M.Z. Papiz.)...

In contrast, the transmembrane helices observed in the reaction center are embedded in a hydrophobic surrounding and are built up from continuous regions of predominantly hydrophobic amino acids. To span the lipid bilayer, a minimum of about 20 amino acids are required. In the photosynthetic reaction center these a helices each comprise about 25 to 30 residues, some of which extend outside the hydrophobic part of the membrane. From the amino acid sequences of the polypeptide chains, the regions that comprise the transmembrane helices can be predicted with reasonable confidence. 

Figure 12.23 Hydropathy plots for the polypeptide chains L and M of the reaction center of Rhodobacter sphaeroides. A window of 19 amino acids was used with the hydrophohicity scales of Kyte and Doolittle. The hydropathy index is plotted against the tenth amino acid of the window. The positions of the transmembrane helices as found by subsequent x-ray analysis by the group of G. Feher, La Jolla, California, ate indicated by the green regions.

Comparison of the amino acid sequences of the L and M subunits of the reaction centers from three different bacterial species shows that about 50% of all residues in those two subunits are conserved in all three species. In the transmembrane helices, sequence conservation varies. Residues that are buried and have contacts either with pigments or with other transmembrane helices are about 60% conserved. In contrast, residues that are fully exposed to the membrane lipids are only 16% conserved. Clearly, fewer restrictions... 

Table 12.2 Amino acid sequences of the transmembrane helices of the photosynthetic reaction center in Rhodobacter sphaeroides...

The most important general lesson is that there are hydrophobic transmembrane helices, the positions of which within the amino acid sequence can be predicted with reasonable accuracy. This applies both to the single transmembrane-spanning helix within the H polypeptide chain of the reaction center and the five transmembrane helices of the L and M chains that... 

Like the photosynthetic reaction center and bacteriorhodopsin, the bacterial ion channel also has tilted transmembrane helices, two in each of the subunits of the homotetrameric molecule that has fourfold symmetry. These transmembrane helices line the central and inner parts of the channel but do not contribute to the remarkable 10,000-fold selectivity for K+ ions over Na+ ions. This crucial property of the channel is achieved through the narrow selectivity filter that is formed by loop regions from thefour subunits and lined by main-chain carbonyl oxygen atoms, to which dehydrated K ions bind. 

Figure 13.2 Activated G protein receptors, here represented as seven red transmembrane helices, catalyze the exchange of GTP for GDP on the Gapy trimer. The then separated Ga-GTP and Gpy molecules activate various effector molecules. The receptor is embedded in the membrane, and Ga, Gpy and G py are attached to the membrane by lipid anchors, and they all therefore move in two dimensions. (Adapted from D. Clapham, Nature 379 297-299, 1996.)...

FIGURE 10.5 A model for the arrangement of the glucose transport protein in the erythrocyte membrane. Hydropathy analysis is consistent with 12 transmembrane helical segments. 

FIGURE 10.18 A model for the structure of the a-factor transport protein in the yeast plasma membrane. Gene duplication has yielded a protein with two identical halves, each half containing six transmembrane helical segments and an ATP-binding site. Like the yeast a-factor transporter, the multidrug transporter is postulated to have 12 transmembrane helices and 2 ATP-binding sites. 

The four mammalian ARs are members of the rhodopsin-like Class A family of GPCRs, which contain seven transmembrane helical domains ( TMs). Character istics of the four subtypes of the human ARs, length of their primary sequences, their chromosomal localization, and their signaling pathways are given in Table 1. The A2a receptor is considerably longer than the other three subtypes, due to its extended carboxy-terminal. 

Aquaporins. Figure 1 (a) The hour-glass model. The scheme depicts the six transmembrane helices (H1-H6), the connecting loops A-E, including the helical parts of loops B ((H)B) and E (E(H)), and the conserved NPA (Asn-Pro-Ala) motif of canonical aquaporins. (b) Structure of the conserved NPA motif region, flanked by the indicated helices, (c) Crystallographic structure of AQP1 tetramer. The four water pores in atetramer are indicated [1]. 

Heptahelical domains are protein modules found in all known G-protein coupled receptors, made up of seven transmembrane helices interconnected by three extra and three intracellular loops. For most G-protein coupled receptors activated by small ligands, the binding site is located in a cavity formed by transmembrane domains 3, 5, 6 and 7. 

Alike any other G-protein coupled receptors (GPCRs), mGlu receptors have seven transmembrane helices, also known as the heptahelical domain (Fig. 2). As observed for all GPCRs, the intracellular loops 2 and 3 as well as the C-terminal tail are the key determinants for the interaction with and activation of G-proteins. However, sequence similarity analysis as well as specific structural features make these mGlu receptors different from many other... 

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