SAA3-Retinol Complex
Jack Weber '27

Contents:

I. Introduction

Serum amyloid A (SAA) proteins are a family of apolipoproteins that are primarily produced in the liver that are frequently bound to high-density lipoprotein in the bloodstream. SAA proteins act as retinol-binding proteins that transport retinol during infections. The majority of retinol transported in the bloodstream is bound to the small amount of free SAA that is not associated with HDL.

Retinol is produced in the body from vitamin A absorbed by the intestines, and is stored in the liver in the form of retinyl esters. Vitamin A is a family of molecules that includes retinol, retinyl esters, and related provitamins used to produce it. These retinyl esters are transported around the body as needed by transport proteins such as SAA.

Retinol transportation plays a significant role in immunity because retinol and related molecules regulate multiple immune functions. Retinoic acid is a regulator of TGF-beta-dependent immune responses. Additionally, retinol deficiency is associated with increased risk of infection, further highlighting the molecule’s importance to the function of the immune system.

II. General Structure

Mouse-derived SAA3 protein, the specific type of SAA present in this trimer, has a molecular weight of 15 kDa and a length of 103 amino acids. The serum amyloid A-retinol complex is composed of a retinol molecule bound at the center of a serum amyloid A-3 trimer. In this trimer, the SAA proteins share a conserved structure containing a four-helix bundle that stretches from the N terminus to the C terminus. The amphipathic ⍺1 and ⍺3 helices of the SAA proteins form a V-shaped motif (V motif) with the apolar side forming a hydrophobic cavity between the two helices. Retinol binds to a hydrophobic pocket at the center of the SAA trimer composed of the apolar residues located on the V motifs of the three SAA protomers. 

III. The SAA Trimer

The three chains (,,) of the SAA trimer associate around the hydrophobic surface of the V motif. Chains A and C are rotated by 37 degrees relative to each other, while they are rotated by 172 and 167 degrees relative to chain B, respectively. The three V motifs of the SAA proteins bind cooperatively to form the asymmetric structure of the SAA trimer. The hydrophobic Trp21, Val22, and Met25 residues on the N-terminus side of the α1 helix of chain B associate with the V motif cavity of chain A at the Trp36, Tyr39, Ile76, and Ala79 residues. The N-terminus of the α1 helix of chain A associates with the residues in the edge of α1 helix of chain B rather than interacting with the V motif cavity of chain B. On the C-terminus of the α3 helix of chain A, the Ala82 and Phe86 residues pack into the V motif cavity of chain C, which is formed by the Trp36, Tyr39, Ile76, Ala79, and Val83 residues. This interaction forms the interface between the A and C chains. The α3 helices of chains B and C mediate the interaction of the two chains. The residues that interact between these chains are Trp71, Val75, Ala79, and Ala82 from chain B and Trp71 and Val75 from chain C. 

IV. The Retinol-Binding Pocket

In the SAA trimer, the asymmetric packing of the protomers allows for the formation of a hydrophobic pocket composed of nonpolar amino acid residues in the V motifs of each of the serum amyloid A protomers measuring approximately 17.4 Å × 8.6 Å × 8.9 Å. The residues whose hydrophobic interactions form the pocket include Trp71, Val75, Ala79, Ala82, Val83, and Phe86 from chain A, Phe24, Met25, and Trp71 from chain B, and Met25, Ala28, Trp36, Trp71, Val75, Ile76, and Ala79 from chain C . The retinol molecule is able to fit inside of this pocket and bind to it through hydrophobic interactions, allowing it to be transported throughout the body. The SAA trimer’s retinol binding pocket is similar to that of retinol binding protein, or RBP. This may suggest that the two structures use similar mechanisms to bind retinol to their binding sites. 

V. References

Hu, Z., Bang, Y.-J., Ruhn, K. A., & Hooper, L. V. (2019). Molecular basis for retinol binding by serum amyloid A during infection. Proceedings of the National Academy of Sciences, 116(38), 19077-19082.  https://doi.org/10.1073/pnas.1910713116

Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., & Cheroutre, H. (2007). Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science (New York, N.Y.), 317(5835), 256–260. https://doi.org/10.1126/science.1145697

Sommer A. (2008). Vitamin a deficiency and clinical disease: an historical overview. The Journal of nutrition, 138(10), 1835–1839. https://doi.org/10.1093/jn/138.10.1835 


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