Transmembrane Proteins
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Transmembrane Proteins

October 8, 2019


In the Amino Acids and Protein Structure tutorial,
we talked about the chemistry of protein synthesis and folding. We differentiated between hydrophilic
and hydrophobic amino acids based on the R groups. Because of the hydrophobic effect,
which decreases hydrophobic surface area in order to maximize favorable interactions between
hydrophilic molecules, we saw that proteins that exist in the watery environment of the
cytoplasm have mostly hydrophilic amino acids on the surface, which can form favorable interactions
with water and other hydrophilic molecules in
the cytoplasm. But as mentioned in the Lipid Bilayer tutorial,
some proteins span membranes. Many ions and molecules cannot cross the hydrophobic lipid
bilayer, and these molecules require a transport protein to allow them to pass. In this tutorial,
we’ll explore the chemistry of these transmembrane proteins, which must have distinct domains
appropriate for the distinct environments of the extracellular space, the interior of
the membrane, and the cytoplasm. We’ll also look at the chemical principles that underlie
the specificity of channel proteins. Transport proteins allow ions or molecules
to pass from one side of a membrane to the other. As a result, transport proteins must
be transmembrane proteins; they must span the membrane. Whereas the parts of proteins
that exist in the watery environment of the cell have hydrophilic surface amino acids,
the parts of proteins that cross the lipid bilayer must have hydrophobic surface amino
acids. Because the interior of the bilayer is made of hydrocarbon tails, which are uncharged,
any neighboring hydrophilic amino acids would not get a favorable +/- interaction with the
bilayer. In order to embed in the membrane, these hydrophilic amino acids would have to
break favorable interactions with fully or partially charged molecules of the cytoplasm.
As a result, the part of a polypeptide that crosses the lipid bilayer has hydrophobic
amino acids exposed to the surrounding hydrocarbon tails. These hydrophobic side chains don’t
have to forgo any favorable interactions as they move out of the water, because they don’t
have charges. But what about synthesis of these hydrophobic
domains? Normally, protein synthesis occurs in the cytoplasm of the cell. But the cytoplasm
is hydrophilic, and hydrophobic amino acids, shown here in red, don’t form favorable
interactions with the hydrophilic cytoplasm. This is especially true when there are many
hydrophobic amino acids in a row, which force neighboring water molecules of the cytoplasm
to forgo favorable interactions. Here’s where signal recognition particles, or SRPs,
come in: they recognize a string of hydrophobic amino acids, bind them, and bring them to
the membrane of the endoplasmic reticulum. These hydrophobic sections are signal sequences,
start-transfer sequences, or stop-transfer sequences. Because they are hydrophobic, they
embed in the hydrophobic membrane of the rough ER. This decreases the hydrophobic surface
area that is exposed to the cytoplasm, which allows water and other hydrophilic molecules
to interact favorably with each other instead of foregoing those favorable interactions
to be next to uncharged side chains. But remember that for all amino acids, including
hydrophobic amino acids, the atoms that make up the backbone have partial charges. In this
transmembrane segment, the hydrophobic side chains don’t forgo favorable interactions,
but the partially charged atoms in the backbone would. To maximize stability and decrease
free energy, these partial charges maximize favorable interactions with other partial
charges. This can happen in a variety of ways depending on the structure of the protein.
We’ll look at two scenarios: single-pass transmembrane proteins, as found in receptor
tyrosine kinases, and multi-pass transmembrane proteins, as found in ion channels. In single-pass transmembrane proteins, favorable
interactions between partially charged atoms of the backbone can be maximized by forming
an alpha helix. The backbone, highlighted in blue, coils around so that hydrogen bonds
can be formed between partially negative oxygen atoms and partially positive hydrogen atoms
of amino acids that are four away. Hydrophobic side chains project out into the hydrophobic
phospholipid tails, and all hydrophilic atoms of the backbone are tucked into the inside
of the alpha helix, maximizing favorable interactions. Typically, this alpha helix is 20-25 amino
acids long, so that the length of the hydrophobic alpha helix is the same as the length of the
hydrophobic section of the lipid bilayer. This is the form of the transmembrane section
of each receptor tyrosine kinase in a dimer. Each RTK has an extracellular domain, a transmembrane
domain, and an intracellular domain. Like proteins found in the cytoplasm, both the
extracellular domain and the intracellular domain have hydrophilic side chains exposed
to the watery surroundings. The transmembrane domain is a single alpha helix, and the amino
acids in that alpha helix have hydrophobic side chains. In multi-pass transmembrane proteins, multiple
segments of the polypeptide chain pass through the membrane. For example, the non-gated K+
channel protein, which is involved both in cell transport and in neuron function, has
eight transmembrane alpha helices. These eight alpha helices are arranged into a ring that
forms the pore of the channel. K+ is hydrophilic – it’s a charged ion.
In the extracellular space or in the cytoplasm, K+ forms favorable interactions with water
molecules. We’ve seen these favorable interactions between water and Na+ and Cl- ions in previous
tutorials. For K+ to enter the channel, it must forgo
those favorable interactions with partially negative oxygen atoms of water. Breaking these
interactions is unfavorable, and the only way it’ll happen is if K+ is able to exchange
those interactions for other favorable interactions in the pore of the channel. This is exactly
what happens – the inner lining of the channel is hydrophilic, and it can form favorable
interactions with K+ ions. This includes the opening of the channel as well as the sides
of the alpha helices that form the lining of the pore. Let’s start by looking at the opening of
the channel. At the opening of the channel, K+ ions exchange favorable interactions with
water molecules for favorable interactions with partially negative oxygen atoms of the
protein. The opening of the channel has eight partially negative oxygen atoms that are all
perfectly spaced to fit a K+ ion (I’ve only drawn four of them here). As a result, the
process of moving from water interactions to protein interactions has a small activation
energy – there’s not much of an energy barrier to getting K+ to interact with the
channel. So K+ will and does enter the channel quickly. This K+ channel is specific to K+ ions. It
makes sense that negatively charged ions and hydrophobic molecules wouldn’t enter the
channel, because they wouldn’t interact favorably with the partially negative oxygen
atoms of the protein. It also makes sense that large ions or molecules wouldn’t enter
the channel, because they wouldn’t fit through the pore. But the channel doesn’t even let
in Na+, another positively charged ion that is even smaller than K+. The reason is because Na+ is too small to
interact with all eight of the partially negative oxygen atoms of the pore. As you can see on
the periodic table, Na+ is in the row above K+, and Na+ has one fewer electron shell than
does K+. So Na+ is significantly smaller than K+. If Na+ were to exchange interactions with
water for interactions with the pore of the protein, it wouldn’t get nearly as much
favorable interaction with the protein as it did with water. The diameter of the K+
channel is too wide to fit the Na+ ion. As a result, the process of a Na+ ion moving
from water to the pore of the channel has a high activation energy and thus does not
happen at an appreciable rate. Once inside the channel, K+ forms favorable
interactions with the sides of the alpha helices that line the channel. These transmembrane
alpha helices have one face that is hydrophilic and can thus interact favorably with K+. So unlike single-pass transmembrane
alpha helices, which have all hydrophobic side chains, the alpha helices in K+ channels
have one side that is hydrophobic and one side that is hydrophilic. As a result, channel proteins are inverted
relative to cytoplasmic proteins that we’ve looked at before. While proteins that exist
in the watery environment of the cytoplasm have hydrophilic surfaces and hydrophobic
interiors, channel proteins have hydrophobic surfaces and hydrophilic interiors.

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