Transmembrane loops

This clone, however, had only 56% homology at the amino acid level to the clone described by Boulay et al., and it has since been shown actually to encode the IL-8 receptor, which is also a G-protein-linked receptor with seven transmembrane loops (see Fig. 3.2). 

Antihistamines are antagonists of histamine receptors that displace histamine competitively from its receptors and block the effects of histamine. Histamine receptors, in turn, are G-protein-coupled receptors (GPCRs) that contain the typical seven-transmembrane loop motif. Other common GPCRs include calcium channel receptors, andrenergic ai, dopamine D2, serotonin 5-HT2 and muscarinic receptors. They have... 

Stroop, S.D. et al. (1996) Determinants for calcitonin analog inceracti with the cakitonin receptor N-terminus and transmembrane-loop regions. Endocrinology. 137,4752-4756. 

The H2 receptor is a 359-amino-acid protein in humans. It has some features similar to the Hi protein (e.g., N-terminal glycosylation sites) and phosphorylation sites in the C-terminal. An aspartic acid residue in the third transmembrane loop appears to be critical to agonist and antagonist binding, and threonine/aspartate and tyrosine/aspartate couples in the fifth transmembrane domain appear to be important for interaction of the imidazole part of the histamine molecule. It is positively coupled via Gas to activate adenylyl cyclase for synthesis of cyclic adenosine monophosphate (cAMP) as a second messenger. In some systems, it is coupled through Gq proteins to stimulate phospholipase C. It appears in some cells that other processes, such as breakdown of phosphoinositides, control of intracellular calcium ion levels, and phospholipase A2 activity, can be regulated by other cAMP-independent pathways. 

Example Molecular dynamics simulations of selected portions of proteins can demonstrate the motion of an amino acid sequence while fixing the terminal residues. These simulations can probe the motion of an alpha helix, keeping the ends restrained, as occurs n atiirally m transmembrane proteins. You can also investigate the conformations of loops with fixed endpoints. 

Fig. 5. Schematic diagram of the presumed arrangement of the amino acid sequence for the 5-opioid receptor, showing seven putative transmembrane segments three intracellular loops, A three extracellular loops, B the extracellular N-terrninus and the intracellular C-terrninus, where (0) represents amino acid residues common to ] -, 5-, and K-receptors ( ), amino acid residues common to all three opioid receptors and other neuropeptide receptors and (O), other amino acids. Branches on the N-terruinal region indicate possible glycosylation sites, whereas P symbols in the C-terminal region indicate...

Figure 12.1 Four different ways in which protein molecules may be bound to a membrane. Membrane-bound regions are green and regions outside the membrane are red. Alpha-helices are drawn as cylinders and P strands as arrows. From left to right are (a) a protein whose polypeptide chain traverses the membrane once as an a helix, (b) a protein that forms several transmembrane a helices connected by hydrophilic loop regions,...

Since the outside of the barrel faces hydrophobic lipids of the membrane and the inside forms the solvent-exposed channel, one would expect the P strands to contain alternating hydrophobic and hydrophilic side chains. This requirement is not strict, however, because internal residues can be hydrophobic if they are in contact with hydrophobic residues from loop regions. The prediction of transmembrane p strands from amino acid sequences is therefore more difficult and less reliable than the prediction of transmembrane a helices. 

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 L and the M subunits are firmly anchored in the membrane, each by five hydrophobic transmembrane a helices (yellow and red, respectively, in Figure 12.14). The structures of the L and M subunits are quite similar as expected from their sequence similarity they differ only in some of the loop regions. These loops, which connect the membrane-spanning helices, form rather flat hydrophilic regions on either side of the membrane to provide interaction areas with the H subunit (green in Figure 12.14) on the cytoplasmic side and with the cytochrome (blue in Figure 12.14) on the periplasmic side. The H subunit, in addition, has one transmembrane a helix at the car-boxy terminus of its polypeptide chain. The carboxy end of this chain is therefore on the same side of the membrane as the cytochrome. In total, eleven transmembrane a helices attach the L, M, and H subunits to the membrane. 

The structure of the reaction center also established that membrane-spanning helices can be tilted with respect to the plane of the membrane and that their relative positions within the membrane might be determined by the way they are anchored to the loop regions. Finally, several structures provide examples of how binding pockets for ligands are formed between such transmembrane-spanning helices. 

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. 

Hydrophobicity plots of AQPs indicated that these proteins consist of six transmembrane a-helices (Hl-H6 in Fig. la) connected by five connecting loops (A-E), and flanked by cytosolic N- and C-termini. The second half of the molecule is an evolutionary duplicate and inverse orientation of the first half of the molecule. Loops B and E of the channel bend into the membrane with an a-helical conformation (HB, HE in Fig. lb) and meet and each other at their so-called Asn-Pro-Ala (NPA) boxes. These NPA motifs are the hallmark of AQPs and form the actual selective pore of the channel, as at this location, the diameter is of that of a water molecule (3 A Fig. la and b). Based on the narrowing of the channel from both membrane sides to this small... 

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]. 

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