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The QTY Code is a design method to transform membrane proteins that are intrinsically insoluble in water into variants with water solubility, while retaining their structure and function.

Similar structures of amino acids

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The QTY Code is based on two key molecular structural facts: 1) all 20 natural amino acids are found in alpha-helices regardless of their chemical properties, although some amino acids have a higher propensity to form an alpha-helix; and, 2) several amino acids share striking structural similarities despite their very different chemical properties. These may be paired as: Glutamine (Q) vs Leucine (L); Threonine (T) vs Valine (V) and Isoleucine (I); and Tyrosine (Y) vs Phenylalanine (F).[1][2]

Shapes of the 20 natural amino acids as they appear in an experimental electron density map at 1.5 angstrom resolution.

The QTY Code systematically replaces water-insoluble amino acids (L, V, I and F) with water-soluble amino acids (Q, T and Y) in transmembrane alpha-helices.[3] Thus, its application to membrane proteins changes the water-insoluble form of membrane proteins into water-soluble variants.[3][4] The QTY Code was specifically conceived to render G protein-coupled receptors (GPCRs) into a water-soluble form. Despite substantial transmembrane domain changes, the QTY variants of GPCRs maintain stable structure and ligand binding activities.[3][4][5][6][7]

Hydrogen bond interactions between water and the amino acids (Courtesy of Michael Skuhersky, MIT)

Hydrogen bond interactions between water and the amino acids

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The side chain of glutamine (Q) can form 4 hydrogen bonds with 4 water molecules. There are 2 hydrogen donors from nitrogen and 2 hydrogen acceptors for oxygen. The –OH group of threonine (T) and tyrosine (Y) can form 3 hydrogen bonds with 3 water molecules (2 H-acceptors and 1 H-donor).[1] Color code: Green = carbon, red = oxygen, blue = nitrogen, gray = hydrogen, yellow disks = hydrogen bonds.

The QTY code and how it replaces L, V, I, and F with Q, T, and Y. (A) Crystallographic electronic density maps of the following amino acids: leucine (L), asparagine (N), glutamine (Q), isoleucine (I), valine (V), threonine (T), phenylalanine (F), and tyrosine (Y).
Illustration of the QTY Code.

Three types of alpha-helices and with nearly identical molecular structure

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There are 3 types of alpha-helices and with nearly identical molecular structure, namely: a) 1.5Å per amino acid rise, b) 100˚ per amino acid turn, c) 3.6 amino acids and 360˚ per helical turn, and d) 5.4Å per helical turn. The 3 types of alpha-helices are: 1) mostly hydrophobic amino acids including Leucine (L), Isoleucine (I), Valine (V), Phenylalanine (F), Methionine (M) and Alanine (A) that are commonly found as the helical transmembrane segments in membrane proteins; 2) mostly hydrophilic amino acids including Aspartic acid (D), Glutamic acid (E), Glutamine (Q), Lysine (K), Arginine (R), Serine (S), Threonine (T), Tyrosine (Y) that are commonly found on the out layer in water-soluble globular proteins; 3) mixed hydrophobic and hydrophilic amino acids that are partitioned in 2 faces: hydrophobic face and hydrophilic face, in an analogy, like our fingers with front and back. These alpha-helices sometimes attach to surface of membrane lipid bilayer, or partially buried to the hydrophobic core and partially close to the surface of water-soluble globular proteins.[2]

The QTY code

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The QTY Code is likely universally applicable and also reversible, namely, Q changes to L, T changes to V and I, and Y changes to F. The QTY Code has been successful in designing many water-soluble variants of chemokine receptors and cytokine receptors. The QTY Code may likely be successfully applied to other water-insoluble aggregated proteins. The QTY Code is robust and straightforward: it is the simplest tool to carry out membrane protein design without sophisticated computer algorithms. Thus, it can be used broadly. The QTY Code has implications for designing additional GPCRs and other membrane proteins including cytokine receptors that are directly involved in cytokine storm syndrome.[3][4][5][6][7]

The QTY Code has also been applied to cytokine receptor water-soluble variants with the aim of combatting the cytokine storm syndrome (also called cytokine release syndrome) suffered by cancer patients receiving CAR-T therapy. This therapeutic application may be equally applicable to severely infected COVID-19 patients, for whom cytokine storms often lead to death.[7]

References

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  1. ^ a b Stryer, Lubert (January 1, 1981). Biochemistry (2 ed.). W.H. Freeman and Company.
  2. ^ a b Branden, Carl Ivar; Tooze, John (January 1, 1999). Introduction to Protein Structure (2 ed.). Garland Science. ISBN 9780815323051.
  3. ^ a b c d Zhang, Shuguang; Tao, Fei; Qing, Rui; Tang, Hongzhi; Skuhersky, Michael; Corin, Karolina; Tegler, Lotta; Wassie, Asmamaw; Wassie, Brook; Kwon, Yongwon; Suter, Bernhard; Entzian, Clemens; Schubert, Thomas; Yang, Ge; Labahn, Jörg; Kubicek, Jan; Maertens, Barbara (September 11, 2018). "QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities". PNAS. 115 (37): E8652–E8659. Bibcode:2018PNAS..115E8652Z. doi:10.1073/pnas.1811031115. PMC 6140526. PMID 30154163.
  4. ^ a b c Qing, Rui; Skuhersky, Michael; Chung, Haeyoon; Badr, Myriam; Schubert, Thomas; Zhang, Shuguang (December 17, 2019). "QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity". PNAS. 116 (51): 25668–25676. Bibcode:2019PNAS..11625668Q. doi:10.1073/pnas.1909026116. PMC 6926000. PMID 31776256.
  5. ^ a b Hao, Shilei; Jin, David; Zhang, Shuguang; Qing, Rui (9 April 2020). "QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands". QRB Discovery. 1: e4. doi:10.1017/qrd.2020.4. PMC 7419741. PMID 34192260.
  6. ^ a b Tegler, Lotta; Corin, Karolina; Pick, Horst; Brookes, Jennifer; Skuhersky, Michael; Vogel, Horst; Zhang, Shuguang (7 December 2020). "The G protein coupled receptor CXCR4 designed by the QTY code becomes more hydrophilic and retains cell signaling activity". Scientific Reports. 10 (1): 21371. Bibcode:2020NatSR..1021371T. doi:10.1038/s41598-020-77659-x. PMC 7721705. PMID 33288780.
  7. ^ a b c Qing, Rui; Tao, Fei; Chatterjee, Pranam; Yang, Gaojie; Han, Qiuyi; Chung, Haeyoon; Ni, Jun; Suter, Bernhard; Kubicek, Jan; Maertens, Barbara; Schubert, Thomas; Blackburn, Camron; Zhang, Shuguang (18 December 2020). "Non-full-length Water-Soluble CXCR4QTY and CCR5QTY Chemokine Receptors: Implication for Overlooked Truncated but Functional Membrane Receptors". iScience. 23 (12): 101670. Bibcode:2020iSci...23j1670Q. doi:10.1016/j.isci.2020.101670. PMC 7756140. PMID 33376963.

Further reading

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