Transmembrane pores

Fig. 3. (a) Chemical stmcture of a synthetic cycHc peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the dat rings are hydrophobic and allow insertion into Hpid bilayers, (b) Proposed stmcture of a self-assembled transmembrane pore comprised of hydrogen bonded cycHc peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in Hpid bilayers (71). 

Aeromonas hydrophila is a bacterium that causes diarrheal diseases and deep wound infections. These complications arise due to pore formation in sensitive cells by the protein toxin aerolysin. Proteolytic processing of the 52-kD precursor proaerolysin (Figure 10.34) produces the toxic form of the protein, aerolysin. Like a-hemolysin, aerolysin monomers associate to form a heptameric transmembrane pore. Michael Parker and coworkers have proposed... 

Song, L., Hobangh, M., Shnstak, C., et al., 1996. Structure of staphylococcal o -hemolysin, a heptameric transmembrane pore. Science 274 1859 -1866. 

ATP synthase actually consists of two principal complexes. The spheres observed in electron micrographs make up the Fj unit, which catalyzes ATP synthesis. These Fj spheres are attached to an integral membrane protein aggregate called the Fq unit. Fj consists of five polypeptide chains named a, j3, y, 8, and e, with a subunit stoichiometry ajjSaySe (Table 21.3). Fq consists of three hydrophobic subunits denoted by a, b, and c, with an apparent stoichiometry of ajbgCg.ig- Fq forms the transmembrane pore or channel through which protons move to drive ATP synthesis. The a, j3, y, 8, and e subunits of Fj contain 510, 482, 272, 146, and 50 amino acids, respectively, with a total molecular mass... 

The AChR is composed of five subunits, ql2Pi - A neurotoxin attaches to the a subunit. Since there are 2 mol of the a subunits, 2 mol of neurotoxins attach to 1 mol of AChR. A neurotransmitter, acetylcholine (ACh), also attaches to the a subunit. When the ACh attaches to the AChR, the AChR changes conformation, opening up the transmembrane pore so that cations (Na" ", K ) can pass through. By this mechanism the depolarization wave from a nerve is now conveyed to a muscle. The difference between neurotoxin and ACh is that the former s attachment does not open the transmembrane pore. As a consequence, the nerve impulse from a nerve cannot be transmitted through the postsynaptic site (27). 

It is now recognised that a wide range of organic molecules, collectively termed ionophores 185,186) or complexones 187), are able to facilitate ion (usually cation) transport. Two major mechanisms have been revealed for this process, namely the involvement of transmembrane ion carriers and transmembrane pores or channels (see Fig. 19). The majority of ionophores studied to date are natural antibiotics and their synthetic analogues which are, on a biological scale, comparatively small molecules lending themselves to study outside the biological system. In contrast far less is known about the molecular structures involved in normal transport processes. Such molecules are likely to be more complex or present in small amounts and may require... 

The association of host defense peptides with lipid bilayers has been observed to be directly related to the ratio of peptide to lipid. At low peptide/lipid ratios, peptides are oriented parallel to the membrane. As the ratio increases, the peptides reorient themselves perpendicular to the membrane, ultimately inserting into the bilayer. Following membrane insertion transmembrane pores are formed. The insertion of peptides into the lipid membrane and subsequent translocation of peptides into the cytoplasm or formation of transmembrane pores has been described by multiple models of host defense peptide insertion. 

It was known that large organic cations such as the tetraethylammonium (TEA) ion and large inactivation peptides (part of the p subunit—T1 assembly) enter the transmembrane pore and the question arises as to how that would take place given the T1 domain s narrow central core. These researchers answer the question in reference 16 through their analysis of the structure and function at the cytoplasmic interface (the connection region between the a and P subunits). 

Channels Transmembrane pores selectivity for solutes depends on biophysical properties that are actively regulated... 

Notman, R., Anwar, J., Briels, W.J., Noro, M.G., den Otter, W.K. Simulations of skin barrier function free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers. Biophys. J. 2008, 95, 4763-71. 

It is generally agreed that activation of ion charmels is caused by a voltage-induced conformational change that opens a transmembrane pore. It is assumed that the ion charmel contains a structural element that can register changes in the electrical field. 

FIGURE 11-46 Structure of an aquaporin, AQP-1. The protein is a tetramer of identical monomeric units, each of which forms a transmembrane pore (derived from PBD ID 1J4N). (a) Surface model viewed perpendicular to the plane of the membrane. The protein contains four pores, one in each subunit. (The opening at the junction of the subunits is not a pore.) (b) An AQP-1 tetramer, viewed in the plane of the membrane. The helices of each subunit cluster around a central transmembrane pore. In each monomer, two short helical loops, one between helices 2 and 3 and the other between 5 and 6, contain the Asn-Pro-Ala (NPA) sequences found in all aquaporins, and form part of the water channel, (c) Surface representation of a single subunit, viewed in the plane of the membrane. The near side of the AQP-1... 

We find an answer in the structure of AQP-1, as determined by x-ray diffraction analysis (Fig. 11-46). AQP-1 has four monomers (each Mr 28,000) associated in a tetramer, each monomer forming a transmembrane pore with a diameter (2 to 3 A) sufficient to allow passage of water molecules in single file. Each monomer consists of six transmembrane helical segments and two shorter helices, each of which contains the sequence Asn-Pro-Ala (NPA). The NPA-containing short helices extend toward the middle of the bilayer from opposite... 

This picture was made by mathematically filtering electron micrographs of ordered, two-dimensional arrays of the receptor. Each of the four pentameric structures shown represents an individual acetylcholine receptor with its central transmembrane pore. The dark areas indicate the five subunits (a2fiy8). (From R. M. Stroud, M. P. McCarthy, and M. Schuster, Nicotinic acetylcholine receptor superfamily of ligand-gated ion channels,... 

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