Molecular Biology: Protein Structure and Functions - Stepanov V.M. 2005

Tertiary Protein Structure
Structural Features of Membrane Proteins

The statements above apply to Globular Proteins functioning in an aqueous environment, such as cytosolic and secretory proteins. Different principles govern the structural formation of Membrane Proteins, specifically integral proteins that span the membrane. Proteins localized on the membrane surface feature a specialized hydrophobic domain acting as an anchor, or another hydrophobic Structure, such as a covalently linked lipid moiety; otherwise, their spatial conformation is determined by the standard rules common to all proteins. Integral proteins, whose incorporation into the membrane occurs co-translationally, apparently cannot maintain their native structure in a purely aqueous environment at all. They contain multiple transmembrane segments, predominantly formed by a-helix stretches rich in hydrophobic Amino Acids. These segments are connected by extramembranous loops facing both the Cytosol and the external environment (Fig. 6.10).

External loops in the membrane proteins of eukaryotes are typically heavily glycosylated, which enhances their hydrophilicity. Intramembrane a-helices can contact one another to form bundles; however, they do not form an internal Hydrophobic core. The driving factor for its formation is also absent, as the transmembrane Regions of the protein do not come into contact with Water.

Consequently, a greater role in maintaining a unified structure may be played by Van der Waals forces (acting between the side chains of amino acids that form the a-helices), Electrostatic Interactions of ionized groups embedded in a non-polar environment, and the dipoles intrinsic to a-helices. Disulfide Bonds connecting the transmembrane a-helices may also play a certain role. Finally, extramembranous domains, by forming their structure according to standard rules, can act as structural organizers and stabilize the integrity of the Tertiary Structure of these proteins. Transmembrane regions can also adopt a ß-Structure.

Class="center">

Fig. 6.10A. Hypothetical scheme of the orientation of Structural elements of a transmembrane protein — the ß₂-adrenergic receptor in the membrane.

The membrane (shaded) is spanned by seven a-helical segments very rich in hydrophobic amino acids. The loops shown at the top of the figure project into the extracellular space and participate in effector binding; those at the bottom face the cytosol and mediate interaction with the signal-transducing G protein. Cysteine residues are shown in black.

Fig. 6.10B. Hypothetical scheme of the orientation of structural elements of a transmembrane protein — the ß₂-adrenergic receptor in the membrane.

The same scheme viewed from the extracellular side; S denotes the sulfur atoms of cysteine or cystine. Solid lines indicate extracellular regions of the polypeptide chain, while dashed lines indicate intracellular regions.

Investigating the Structure of Transmembrane proteins—which perform such vital Functions as the Transport of Molecules into The Cell, intercellular interactions, The formation of Ion Channels, and the transmission of external signals into the cell—is extremely challenging. In certain cases, crystals can be obtained by replacing their natural lipid environment with a synthetic surfactant. Further study of such crystals proceeds via standard Methods. In more complex situations, researchers resort to Limited proteolysis, which cleaves the extramembranous regions of the polypeptide chain, or to chemical modification targeted at these same regions. The overall folding of Secondary structure elements can be observed using Electron Microscopy.