Third transmembrane helix

Chin C, Murphy J, Huffman J, Kendall D (1999) The third transmembrane helix of the cannabinoid receptor plays a role in the selectivity of aminoalkylindoles for CB2, peripheral cannabinoid receptor. J Pharmacol Exp Ther 291 837-844... 

Each subunit has two transmembrane a helices as well as a third, shorter helix that contributes to the pore region. The outer cone is formed by one of the transmembrane helices of each subunit. The inner cone, formed by the other four transmembrane helices, surrounds the ion channel and cradles the ion selectivity filter. 

This technology allows the sensitive analysis of small conformational changes and will ultimately allow an understanding of the receptor activation mechanism. These studies have shown two distinct switch mechanisms in the / -adrenergic receptor, both located in the third intracellular loop and the cytoplasmic end of transmembrane helix VI an ionic lock mechanism that involves an interaction of the cytoplasmic ends of helix VI and helix III (and is reported by a label in position 271 of the receptor), and a rotamer toggle switch mechanism that is reported by a label in position 265 (Yao et al, 2006). 

After synthesis of the first two transmembrane a helices, both ends of the nascent chain face the cytosol and the loop between them extends into the ER lumen. The C-terminus of the nascent chain then continues to grow into the cytosol, as it does in synthesis of type 1 and type 111 proteins. According to this mechanism, the third a helix acts as another type 11 signal-anchor sequence, and the fourth as another stop-transfer anchor sequence (see Figure 16-13d). Apparently, once the first topogenic sequence of a multipass polypeptide initiates association with the translocon, the ribosome remains attached to the translocon, and topogenic sequences that subsequently emerge from the ribosome are threaded into the translocon without the need for the SRP and the SRP receptor. 

One letter amino acid codes are used in the second column (AA). Predicted structure (PS) in the third column can be a-helix (H), P-sheet (B) or coil (C) structure that includes turn and undefined structure. Residues predicted in the transmembrane helix configuration (PTM) in the fourth column are labeled with letter NT except for highly probable TMH conformation when letter O is used. Residues with a potential to form transmembrane P-strands are labeled with letter E in the fourth column. The coil (C) conformation from third column is specified as undefined (U) or turn (T) conformation in the fourth column. Fifth to eighth column contain smoothed preferences for a-helix (PH), P-sheet (PB), turn (PT) and undefined (PU) conformation. The columns 9 and 10 contain numerical values for hydrophobic moments calculated in the case of assumed a-helix configuration (MA) and for moments calculated for assumed P-sheet configuration (MB). Last two columns contain PH-PT difference of preferences (H-T) that helps in visual identification of predicted transmembrane helices and PB+MB-2.0 scores that help in prediction of potential membrane-embedded P-strands. 

The hexose-6-phosphate transporter UhpT protein also contains 12 transmembrane (TM) regions. Based on experimental data, Hall and Maloney [113] conclude that TM11 spans the membrane as an a-helix with approximately two-thirds of its surface lining a substrate translocation pathway. It is suggested that this feature is a general property of carrier proteins in the Major Facilitator Superfamily, and that, for this reason, residues in TM11 will serve to carry determinants of substrate selectivity [113]. 

The crystal structure of reaction centers from R. viridis was determined by Hartmut Michel, Johann Deisenhofer, Robert Huber, and their colleagues in 1984. This was the first high-resolution crystal structure to be obtained for an integral membrane protein. Reaction centers from another species, Rhodobacter sphaeroides, subsequently proved to have a similar structure. In both species, the bacteriochlorophyll and bacteriopheophytin, the iron atom and the quinones are all on two of the polypeptides, which are folded into a series of a helices that pass back and forth across the cell membrane (fig. 15.1 la). The third polypeptide resides largely on the cytoplasmic side of the membrane, but it also has one transmembrane a helix. The cytochrome subunit of the reaction center in R. viridis sits on the external (periplasmic) surface of the membrane. 

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