Molecule of the Month: Phospholipase A2

Phospholipase A2 breaks membrane lipids, forming molecules that contribute to inflammation and pain signaling.

Pancreatic phospholipase A2, with calcium in green and cysteine sulfur atoms in yellow.
Pancreatic phospholipase A2, with calcium in green and cysteine sulfur atoms in yellow.
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Over 100 years ago, scientists discovered that an enzyme in snake venom breaks the lipid molecules in cellular membranes. Since then, scientists have discovered similar enzymes in many other places. Some types of phospholipase A2 are secreted, such as the phospholipases made by the pancreas for use in digestion. Others are made inside cells, where they help with creation of signaling molecules. All of them share a similar function of chopping off one of the tails of phospholipids.

Small and Steady

Snake venom phospholipases and pancreatic phospholipases are small enzymes that can withstand the unfriendly environment when they are secreted (or injected) outside of cells. They are glued together by a collection of disulfide linkages that stabilize the folded structure. The one shown here, from cow pancreas (PDB entry 1bp2), has seven crosslinks. The active site is a pocket on one side of the protein, with a calcium ion that assists with the cleavage reaction.

Inflammatory Response

Some of the lipid tails that are released by phospholipase A2 are used to build signaling molecules involved in inflammation and pain. Because of this action, disorders in phospholipase action can contribute to important diseases such as atherosclerosis and Crohn’s disease. The research community is currently using the structures of phospholipases to discover new drugs to fight these diseases by blocking the action of the enzyme.
Pancreatic and cytosolic phospholipase A2. A membrane is shown schematically in gray.
Pancreatic and cytosolic phospholipase A2. A membrane is shown schematically in gray.
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Inside and Out

Many different forms of phospholipase A2 are made for different functions. Secreted phospholipase A2 is small, whereas the cytoplasmic enzymes are larger, with separate domains that are involved with interaction with membranes and catalyzing the cleavage reaction (shown here from PDB entry 1cjy). These enzymes all have regions on their surface that interact with the face of a membrane, allowing the enzyme to extract lipids for cleavage.

Exploring the Structure

Venom Phospholipase A2

Two venom phospholipases are shown here, one from bee venom (PDB entry 1poc) and one from cobra venom (1pob). The structures of these two enzymes are quite different, but they share a very similar collection of active site amino acids, including a histidine that attacks the lipid bond that is cleaved and an aspartate that coordinates the calcium ion. These structures have an analog of the phospholipid bound in the active site, showing how everything lines up to perform the reaction in these two different enzymes. To explore these structures in more detail, click on the image for an interactive Jmol.

Topics for Further Discussion

  1. Some forms of phospholipase A2 associate into larger assemblies, although it is not known if these have a biological function. Take a look at entry 1psh to see a trimeric form of cobra toxin.
  2. Structures of many types of phospholipase are available in the PDB archive, including some with trial inhibitors. Try searching for “Phospholipase A2” in the main PDB site.

Related PDB-101 Resources

References

  1. Dennis, E.A., Cao, J., Hsu, Y.-H., Magrioti, V., Kokotos, G. (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem. Rev. 111: 6130-6185.
  2. 1c1j: Zhang, H.-l., Zhang, Y.-Q., Song, S.-Y., Zhou, Y., Lin, Z.-J. (1999) Structure of Cadmium-substituted Phospholipase A2 from Agkistrodon halys Pallas at 2.8 Angstroms Resolution. Protein Pept. Lett. 6: 185-193.
  3. 1pob, 1poc: Scott, D.L., Otwinowski, Z., Gelb, M.H., Sigler, P.B. (1990) Crystal structure of bee-venom phospholipase A2 in a complex with a transition-state analogue. Science 250: 1563-1566.
  4. 1bp2: Dijkstra, B.W., Kalk, K.H., Hol, W.G., Drenth, J. (1981) Structure of bovine pancreatic phospholipase A2 at 1.7A resolution. J. Mol. Biol. 147: 97-123.

November 2019, David Goodsell

http://doi.org/10.2210/rcsb_pdb/mom_2019_11
About Molecule of the Month
The RCSB PDB Molecule of the Month by David S. Goodsell (The Scripps Research Institute and the RCSB PDB) presents short accounts on selected molecules from the Protein Data Bank. Each installment includes an introduction to the structure and function of the molecule, a discussion of the relevance of the molecule to human health and welfare, and suggestions for how visitors might view these structures and access further details.More