Proteins reside in membranes by means of hydrophobic regions

KEY TERMS:

• The transmembrane region (transmembrane domain) is the part of a protein that spans the membrane bilayer. It is hydrophobic and in many cases contains approximately 20 amino acids that form an α-helix. It is also called the transmembrane domain.
• A transmembrane protein (Integral membrane protein) extends across a lipid bilayer. A hydrophobic region (typically consisting of a stretch of 20-25 hydrophobic and/or uncharged aminoa acids) or regions of the protein resides in the membrane. Hydrophilic regions are exposed on one or both sides of the membrane.

KEY CONCEPTS:

• Group I proteins have the N-terminus on the far side of the membrane; group II proteins have the opposite orientation.
• Some proteins have multiple membrane-spanning domains.  

All biological membranes contain proteins, which are held in the lipid bilayer by noncovalent interactions. The operational definition of an integral membrane protein is that it requires disruption of the lipid bilayer in order to be released from the membrane. A common feature in such proteins is the presence of at least one transmembrane domain, consisting of an α-helical stretch of 21-26 hydrophobic amino acids. A sequence that fits the criteria for membrane insertion can be identified by a hydropathy plot, which measures the cumulative hydrophobicity of a stretch of amino acids. A protein that has domains exposed on both sides of the membrane is called a transmembrane protein. The association of a protein with a membrane takes several forms (see 32.5 Membranes and membrane proteins). The topography of a membrane protein depends on the number and arrangement of transmembrane regions.

When a protein has a single transmembrane region, its position determines how much of the protein is exposed on either side of the membrane. A protein may have extensive domains exposed on both sides of the membrane or may have a site of insertion close to one end, so that little or no material is exposed on one side. The length of the N-terminal or C-terminal tail that protrudes from the membrane near the site of insertion varies from insignificant to quite bulky.

Figure 8.31 shows that proteins with a single transmembrane domain fall into two classes. Group I proteins in which the N-terminus faces the extracellular space are more common than group II proteins in which the orientation has been reversed so that the N-terminus faces the cytoplasm. Orientation is determined during the insertion of the protein into the endoplasmic reticulum.

Figure 8.32 shows orientations for proteins that have multiple membrane-spanning domains. An odd number means that both termini of the protein are on opposite sides of the membrane, whereas an even number implies that the termini are on the same face. The extent of the domains exposed on one or both sides is determined by the locations of the transmembrane domains. Domains at either terminus may be exposed, and internal sequences between the domains "loop out" into the extracellular space or cytoplasm. One common type of structure is the 7-membrane passage or "serpentine" receptor; another is the 12-membrane passage component of an ion channel.

Does a transmembrane domain itself play any role in protein function besides allowing the protein to insert into the lipid bilayer? In the simple group I or II proteins, it has little or no additional function; often it can be replaced by any other transmembrane domain. However, transmembrane domains play an important role in the function of proteins that make multiple passes through the membrane or that have subunits that oligomerize within the membrane. The transmembrane domains in such cases often contain polar residues, which are not found in the single membrane-spanning domains of group I and group II proteins. Polar regions in the membrane-spanning domains do not interact with the lipid bilayer, but instead interact with one another. This enables them to form a polar pore or channel within the lipid bilayer. Interaction between such transmembrane domains can create a hydrophilic passage through the hydrophobic interior of the membrane. This can allow highly charged ions or molecules to pass through the membrane, and is important for the function of ion channels and transport of ligands. Another case in which conformation of the transmembrane domains is important is provided by certain receptors that bind lipophilic ligands. In such cases, the transmembrane domains (rather than the extracellular domains) bind the ligand within the plane of the membrane.