Membrane-spanning pore

Membrane active natural ion transporters are the prime source of inspiration for the design of synthetic transmembrane transporters. These compounds are valuable examples of self-sorting systems to construct functional membrane spanning pores and transporter ion interactions to facilitate the passage of ions across the membrane. 

All K channels are tetrameric molecules. There are two closely related varieties of subunits for K channels, those containing two membrane-spanning helices and those containing six. However, residues that build up the ion channel. Including the pore helix and the inner helix, show a strong sequence similarity among all K+ channels. Consequently, the structural features and the mechanism for ion selectivity and conductance described for the bacterial K+ channel in all probability also apply for K+ channels in plant and animal cells. 

The putative binding site for local anaesthetic molecules at the sodium channel has been identified as two amino acids in the sixth membrane-spanning segment of domain IV [2]. This binding site is located directly underneath the channel pore and can only be reached from the internal side of the membrane. Because local anaesthetics are applied exterior to the nerve fibre, they have to penetrate the axonal membrane before they can bind to the channel. 

Fig. 3. (A) Model of the proposed pore forming part of K channel subunits. Segments S5 and S6 are possibly membrane-spanning helices. The helices are connected by a hydrophobic segment H5 which may be tucked into the lipid bilayer [48]. H5 is flanked by two proline residues P. Adjacent to these proline residues are amino acid side chains ( ) important for external TEA binding [45,46]. Approximately halfway between these two proline residues are amino acid side chains ( ) affecting internal TEA binding [46,47] and K channel selectivity [48]. (B) Mutations are indicated which affect in Shaker channels external TEA (TEAe) or internal TEA (TEA,) binding. Concentrations of TEA for half block of the wild-type and mutant K channels are given at the right-hand side of the corresponding sequence. Data have been compiled from [45-47].

Fig. 5. Proposed topology of K channel subunits inserted into the membrane. COO carboxy-terminal. The proposed membrane-spanning segments SI-S6 in the core region of channel proteins are displayed linearly. H5 may be part of the K channel pore. The amino-terminal inactivation gate is symbolized by a positively charged ball which could occlude the pore region. The extracellular side is thought to be at top and the intracellular side at bottom.

Leonard, R.J., Labarca, C.G., Chamet, P., Davidson, N., Lester, H.A. Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. Science. 242 1578, 1988. 

Figure 4-4. The domain organization of an integral, transmembrane protein as well as the mechanisms for interaction of proteins with membranes. The numbers illustrate the various ways by which proteins can associate with membranes I, multiple transmembrane domains formed of a-helices 2, a pore-forming structure composed of multiple transmembrane domains 3, a transmembrane protein with a single a-helical membrane-spanning domain 4, a protein bound to the membrane by insertion into the bilayer of a covalently attached fatty acid (from the inside) or 5, a glycosyl phosphatidylinositol anchor (from the outside) 6, a protein composed only of an extracellular domain and a membrane-embedded nonpolar tail 7, a peripheral membrane protein noncova-lently bound to an integral membrane protein.

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