Transmembrane domains are sections of proteins that extend through the lipid bilayer of cell membranes. These domains are primarily constructed from amino acids and typically adopt a helical arrangement. Their presence allows proteins to be anchored within the membrane, providing a means for cells to interact with their environment and carry out numerous internal processes, making them fundamental to the existence and function of all living cells.
Building Blocks and Helical Arrangement
Transmembrane domains are composed predominantly of hydrophobic amino acids, which are non-polar and repel water. This characteristic is important for their integration into the lipid bilayer, as the interior of the membrane is also hydrophobic. Examples of these amino acids include alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, and tyrosine. The specific sequence of these amino acids dictates how the domain will interact with the surrounding lipid environment.
The alpha-helix is the most common structural arrangement for transmembrane domains. In this helical structure, the polypeptide backbone coils, and hydrogen bonds form between the carbonyl and amide groups within the backbone itself. This internal hydrogen bonding stabilizes the helix. The non-polar side chains of the amino acids project outwards from the helix, allowing them to interact favorably with the hydrophobic fatty acid tails of the membrane lipids.
A single alpha-helix requires about 18 to 21 amino acid residues to span the width of a cell’s lipid bilayer. While alpha-helices are the most prevalent, some transmembrane proteins, particularly those found in bacterial outer membranes, can also form beta-barrel structures. These beta-barrels are created by multiple beta-strands that form a cylindrical pore, with hydrophobic residues facing outwards towards the lipid environment. Alpha-helical transmembrane proteins constitute about 27% of all human proteins.
Essential Roles in Cellular Processes
Transmembrane domains play diverse and fundamental roles in cellular activities due to their structure and location within the membrane.
One function involves forming channels that allow specific ions to pass through the impermeable lipid bilayer. These channels, often made of multiple alpha-helices, create a hydrophilic pathway for ions like sodium, potassium, or calcium to move in and out of the cell. This movement is important for nerve impulses and muscle contraction.
Another role of transmembrane domains is in cell signaling, where they act as receptors. These receptor proteins have an extracellular portion that binds to signaling molecules, like hormones or neurotransmitters, outside the cell. The binding event triggers a conformational change that is transmitted through the transmembrane domain to the intracellular portion of the protein, initiating a response inside the cell. For example, receptor tyrosine kinases are single-pass proteins that use a single alpha-helical transmembrane domain to relay signals across the membrane.
Transmembrane domains also facilitate the movement of various molecules across the membrane as transporters. These proteins bind to specific molecules on one side of the membrane and then undergo a shape change to release them on the other side. This process can involve active transport, which requires energy to move molecules against their concentration gradient, or passive transport, which allows molecules to move down their concentration gradient.
Transmembrane domains also serve as anchors, providing structural integrity and connecting the cell membrane to the cytoskeleton or extracellular matrix. This anchoring function helps maintain cell shape, facilitates cell movement, and contributes to cell adhesion within tissues. For example, glycophorin A, a protein found in red blood cell membranes, has a hydrophobic alpha-helical transmembrane domain that helps prevent red blood cells from clumping together.
How Transmembrane Domains Stay Embedded
The stable integration of transmembrane domains within the lipid bilayer is primarily governed by hydrophobic interactions. The non-polar amino acid side chains of the transmembrane domain have a strong affinity for the hydrophobic fatty acid tails that make up the interior of the cell membrane. This interaction minimizes unfavorable contact between the non-polar amino acid residues and the aqueous environment inside and outside the cell. Consequently, the hydrophobic core of the membrane acts as a stable, favorable environment for these domains.
Energy considerations favor this arrangement. When a protein segment with hydrophobic amino acids is placed in an aqueous environment, it disrupts the highly ordered water molecules around it, leading to an energetically unfavorable state. By embedding itself within the lipid bilayer, the transmembrane domain reduces this unfavorable interaction with water, leading to a more stable and lower-energy configuration. This “hydrophobic effect” is a driving force for membrane protein folding and insertion.
Proteins can have single or multiple transmembrane domains. Multi-pass proteins, which cross the membrane multiple times, often have several alpha-helices packed closely together. In these cases, some amino acids with charged or polar side chains may be present within the transmembrane region, but they are shielded from the hydrophobic lipid environment by interacting with other helices in the bundle. This allows the formation of aqueous pores or channels while maintaining overall stability within the membrane.