Biological Membranes - A. N. Ogurtsov 2012

Structure and Functions of Biomembranes
Membrane Proteins
Lipid-Binding Motifs

Peripheral Proteins bind to the membrane either through association with integral proteins or directly by interacting with the Lipids of the bilayer (Figure 35).

A comparison of genes encoding various peripheral proteins has revealed several characteristic lipid-binding motifs in their Structure, some of which are listed in Table 4.

Class="center">Table 4 - Lipid-binding motifs

In the table, phosphatidylinositol derivatives are designated as РIР₂ and РIР₃ (Figure 43), PI-3 denotes the enzyme phosphatidylinositol 3-kinase, PS stands for phosphatidylserine, and PH stands for pleckstrin Homology.

Thus, for instance, the pleckstrin homology (PH) domain, which binds to Two Types of phosphorylated phosphatidylinositols (РIР₂ and РIР₃), is the eleventh most common protein domain in The Human Genome. This domain was originally discovered in pleckstrin, a platelet protein.

Figure 43 - Phosphorylated derivatives of phosphatidylinositol (PI): PIP - phosphatidylinositol 4-phosphate, РIР₂ - phosphatidylinositol 4,5-bisphosphate, РІР₃ - phosphatidylinositol 3,4,5-trisphosphate

The high frequency with which this motif occurs in the human genome indicates that membrane-associated proteins perform many vital Functions.

Other characteristic lipid-binding motifs include the C2 domain, the ankyrin repeat domain, and the FERM domain.

The C2 domain, originally discovered within protein kinase C, acts as a membrane-binding domain in numerous Kinases, Phosphatases, and phospholipases.

Phospholipases serve as an example of Water-soluble Enzymes that become activated upon binding to the polar heads of membrane phospholipids. Phospholipases hydrolyze various bonds within the polar HEAD group (Figure 28). These enzymes play a crucial role in the degradation of damaged or unneeded Cell membranes and are active components of many snake venoms.

The MECHANISM OF ACTION of phospholipase A₂ (Figure 44) illustrates The process of Reversible Binding of a water-soluble enzyme to the membrane and catalysis of reactions at the interface between the aqueous solution and the lipid phase.

Figure 44 - Schematic representation of phospholipase A₂. The arrow indicates the bond being hydrolyzed

When in an aqueous solution, the Active Site of phospholipase A₂, which contains a Ca²⁺ ion, is located deep within the protein's catalytic channel, The surface of which is lined with hydrophobic Amino Acids. The enzyme exhibits the highest affinity for bilayers composed of negatively charged phospholipids, such as phosphatidylethanolamines. This affinity is provided by positively charged lysines and arginines surrounding the entrance to the catalytic channel of phospholipase A₂ (shown in black in Figure 44). The electrostatic binding of phospholipase A₂ to the membrane induces a conformational change in the protein globule, which anchors the enzyme to the phospholipid head groups and opens the hydrophobic channel.

As a result of thermal diffusion, a phospholipid enters the channel from the bilayer, where it binds to the active site of the enzyme through Electrostatic Interactions between the negatively charged head group and the Ca²⁺ ion, correctly orienting the target bond (indicated by the arrow in the figure) relative to the catalytically active amino acids of phospholipase A₂.

METABOLISM/35.html">Selection/41.html">Review Questions and Exercises

1. What proteins are referred to as membrane proteins?

2. What are the three recognized Types of Membrane proteins?

3. What structural parts do integral membrane proteins consist of?

4. What Secondary structure elements do transmembrane domains of integral proteins contain?

5. How do lipid-linked membrane proteins attach to the membrane?

6. How do peripheral membrane proteins bind to the membrane?

7. What are the Structural Features of the transmembrane α-helices in integral membrane proteins?

8. What is the advantage of the dimerization of transmembrane alpha-helices in two Glycophorin A molecules?

9. How does The structure of the Bacteriorhodopsin transmembrane domain determine the Functional Properties of this protein?

10. What is The Role of transmembrane α-helices in the functioning of Ion Channels?

11. How do the structures of the transmembrane domains of porins, as integral membrane proteins, differ from those of other membrane proteins?

12. Which functional groups are referred to as lipophilic anchors?

13. Into what three groups are lipid-anchored proteins divided based on the type of lipophilic anchors they use?

14. What is The basis of the Asymmetry of integral proteins and Glycolipids?

15. What is the reason for the low diffusion rate of membrane proteins compared to that of lipid molecules in Biomembranes?

16. What is the function of lipid-binding motifs in the structure of peripheral membrane proteins?

17. How do biomembranes activate water-soluble phospholipase enzymes?