Transmembrane portion

Figure 8.7 Top Sequence of Api 3 and sites of secretase cleavage. y-Secretase has low specificity, cleaving the amyloid precursor protein (APP) anywhere between residues 39 to 43 of Ap. The transmembrane portion of APP is indicated. Bottom processing of amyloid precursor protein (APP) (A) Normal cleavage within AP region by a-secretase (B) pathogenic cleavage of APP by P- and y-secretase, liberating Ap, which can become incorporated into growing plaques. (Note AP = P-Amyloid Peptide)...

The transmembrane domains have different functions, according to the type of receptor. For ligand-controlled receptors, the function of the transmembrane domain is to pass the signal on to the cytosohc domain of the receptor. For hgand-controlled ion channels, the transmembrane portion forms an ion pore that allows selective passage of ions (see Chapter 16). 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

FIGURE 2—2. A side view of a receptor with seven transmembrane regions is shown here. This is a common structure of many receptors for neurotransmitters and hormones. That is, the string of amino acids goes in and out of the cell several times to create three portions of the receptor first, that part that is outside of the cell (called the extracellular portion) second, the part that is inside the receptor that is inside the cell (called the intracellular portion and finally, the part that traverses the membrane several times (called the transmembrane portion). Throughout this text, this receptor will be represented in a simplified schematic manner with the icon shown in the small box. 

FqFi-ATP synthase is composed of two domains (Fig. 1.10a) a transmembrane portion (Fq), the rotation of which is induced by a proton gradient, and a globular catalytic moiety (Fi) that synthesizes and hydrolyzes ATP. The Fi—ATPase moiety, for which several high-resolution structures with the different ligands are available (e.g., [30, 35, 36]), can synthesize, as well as hydrolyze, ATP. Synthesis has been demonstrated by applying an external... 

Figure 163 Schematic diagram of the transmembrane topology of a hERG subunit. The transmembrane portion of the hERG channel contains the voltage Sensor (comprising SI, S2, S3, and S4) and pore (comprising S5, turret helix, pore helix, selectivity filter, and S6) domains. A complete hERG channel consists of a tetramer of subunits, which fashions a membrane pore.

Halobacteria contain four rhodopsins bacteriorhodopsin, halorhodopsin, sensor-yrhodopsin, and phoborhodopsin (Fig. 4.2A) [11-17]. Bacteriorhodopsin and halorhodopsin are light-driven ion pumps, which act as an outward proton pump and an inward Ch pump, respectively. Sensoryrhodopsin and phoborhodopsin are photoreceptors that act to produce attractant and repellent responses in phototaxis, respectively. These four archaeal rhodopsins have similar structures seven helices constitute the transmembrane portion of the protein, and a retinal chromophore is bound to a lysine residue of the seventh helix via a protonated SchifF base linkage (Fig. 4.1). A negatively charged counterion is present to stabilize the positive charge inside the protein the counterion is an aspartate except for in halorhodopsin, which possesses a chloride ion. In sensoryrhodopsin, interaction with a transmembrane transducer protein raises the pKa of the aspartate, so that the aspartate is protonated at neutral pH. 

A more precise description of the extended conformational change, linking to the transmembrane portion, has recently been derived by comparing the 4.6-A structure of the extracellular domain with the crystal structure of the AChBP. It is found that, to a good approximation, there are two alternative extended conformations of the receptor subunits (one characteristic of either a subunit before activation, and the other characteristic of the... 

Each immunoglobulin class exists in two forms - as secreted and membrane-bound antibody. Membrane exons code for the transmembrane and cytoplasmic portion of membrane immunoglobulin and replace the secretory termini the transmembrane portion itself consists of a stretch of hydrophobic amino acids [107, 108,109,110,111,112,113],... 

The transmembrane portion of the M2 protein from the influenza A virus has been studied in hydrated DMPC lipid bilayers with solid-state NMR.209 Orientational constraints are obtained from the isotopically labeled peptide samples mechanically aligned between thin glass plates. I5N chemical shifts from single-site labeled samples constrain the molecular frame with respect to... 

Fig. 14.11. Top (A) and side (B) views of a schematic representation of an ion channel receptor. Ion channel receptors are pentameric units arranged to form a pore or ion channel. Each subunit consists of four transmembrane-spanning amino acid chains (M1-M4) constructed such that the M2 chain faces the channei. The transmembrane portions are connected by extracellular and intracellular loops. In the serotonin family, only 5-HT3 receptors have been identified as ion channel receptors.

It should be expected, however, that C NMR signals of uniformly or densely Relabeled, fully hydrated membrane proteins could be substantially broadened or sup-pressed at ambient temperature, because their backbone or side-chain carbons of certain residues could undergo local fluctuation motions with either correlation times of the order of less than 10 or 10 -10 Rs that vary depending upon the portions under consideration, especially for flexible residues at the N- and C-terminal residues or loops, respectively, as encountered for bR as described below- Therefore, the above-mentioned approach is not always useful for fully hydrated membrane proteins that could undergo a variety of fluctuation motions. Instead, 3D structural data for transmembrane portions were successfully obtained from N NMR data of uniformly (but not densely) N-labeled proteins in either a mechanically or a magnetically aligned system, as far as such samples were prepared at relatively lower humidity. Still, no structural information is available from residues located at unoriented or flexible N- or C-terminal residues as well as at interhelical loops. 

---