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Molecular struture of ion channels_1

The helix is the most prevalent form and is

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Unformatted text preview: embrane segments (which parts of the protein are embedded in the membrane). The polypeptide backbone is twisted into a helix such that about 20 amino acid residues comprise a length of about 30 angstroms along the helix. Since the cell membrane is also about 30 angstroms wide, a stretch of about 20 amino acids is just sufficient to span the membrane. Below we illustrate other factors which further show that the transmembrane segments of ion channels are formed from helices comprised of ~20 amino acid residues . The molecular structure of the Na+ channel The first voltage gated ion channel whose structure was determined was the Na+ channel. Na+ channels are particularly rich in skeletal muscle and in the electric organ of some eels, the eels that generate hundreds of volts used to stun or even kill their prey. In all cases, a very large glycoprotein was purified and was called the subunit. Messenger RNA was obtained and the full amino acid sequence of the subunit of the Na+ channel was deduced from the sequence of nucleotides of the complementary DNA generated from the mRNA. The Na+ channel protein of the subunit is comprised of about 2000 amino acids and is the product of a single gene. But so what? What can be learned about the structure of the Na+ channel by simply knowing its sequence of amino acids? Luckily there are a few rules that provide major insights into which regions of the protein lie within the lipid membrane and how the protein itself is structurally and functionally organized. Of importance in this regard is the hydrophobicity plot. Each amino acid is placed in the plot as it occurs in the protein and each is assigned a hydrophobicity value, which reflects its ability to interact with water. Recall from the previous discussion of amino acids that nonpolar amino acids are hydrophobic (water hating) and are assigned a high positive value, whereas polar amino acids are hydrophilic and are given a negative value. A running average of these values over several amino acids is then calculated around each amino acid in the protein sequence, and plotted as a function of position along the protein chain. Also recall from the previous description that a sequence of about 20 hydrophobic helictial amino acids would span the cell membrane. Thus, sequences of ~20 hydrophobic amino acids in the hydrophobicity plot represent a transmembrane segment. Let's examine the hydrophobicity plot of a Na+ channel shown in the top panel of Fig. 2 in greater detail. Look first at the pattern of the initial 400 amino acids. Beginning at amino acid #75 and ending at about #225, there is a stretch of about 150 amino acids that are all hydrophobic. Since 30 hydrophobic amino acids would span the membrane, this suggests that there should be 5 membrane spanning segments from 75225. If you look carefully, and use a little imagination, you can also see 5 little peaks in this region. Each "peak" is about 20 amino acids long, and each is indicated by a colored box above that span from amino acid 75225. We refer to these peaks as a segment (S), and they are labeled S1S5, as 2 shown above each colored box and in the middle panel of Fig. 2. This is followed by a short span of 100 hydrophilic residues, from about #225325, followed by about more 30 hydrophobic residues. The last set of hydrophobic residues thus forms a sixth transmembrane segment and is labeled S6 (magenta box) in Fig. 2. These 6 transmembrane segments are collectively called domain I, and it is apparent that three other domains, labeled domains II, III and IV, closely resemble domain I, in that domains IIIV also contain six transmembrane segments. Figure 2. Top panel hydrophobicity plot of the amino acid sequence of a Na+ channel. The colored regions show the hydrophobic amino acids. The hydrophobic amino acids show a series of peaks, where each peak is assigned a colored box, where each colored box represents a transmembrane segment. There is a repeating pattern such that series of 6 peaks is repeated four times. Each series of 6 peaks is a domain of the channel. Middle panel: linear arrangement of transmembrane segments from amino acid sequence and hydrophobicity plot. Lower panel: top view...
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