Abstract
The polypeptide backbone of proteins is held together by two main types of covalent bonds: the peptide bonds that link the amino acid residues and the disulfide bonds that link pairs of cysteine amino acids. Disulfide bonds form as a protein folds in the cell and formation was assumed to be complete when the mature protein emerges. This is not the case for some secreted human blood proteins. The blood clotting protein, fibrinogen, and the protease inhibitor, α2-macroglobulin, exist in multiple disulfide-bonded or covalent states in the circulation. Thousands of different states are predicted assuming no dependencies on disulfide bond formation. In this study, probabilities for disulfide bond formation are employed to estimate numbers of covalent states of a model polypeptide with reference to α2-macroglobulin. When disulfide formation is interdependent in a protein, the number of covalent states is greatly reduced. Theoretical estimates of the number of states will aid the conceptual and experimental challenges of investigating multiple disulfide-bonded states of a protein.
Highlights
Most disulfide bonds in mammalian proteins were acquired in vertebrate ancestors and retained as the proteins evolved [1]
Results and Discussion α2-Macroglobulin is an abundant broad-spectrum endopeptidase inhibitor [3] produced by liver hepatocytes and macrophages that circulates in blood and functions in several biological systems [4]
Region and become entrapped due to large conformational transitions in the inhibitor. These transitions expose a cysteine–glutamine thioester bond in α2-macroglobulin that is cleaved by lysine residues of proteases, resulting in their covalent attachment to the inhibitor
Summary
Most disulfide bonds in mammalian proteins were acquired in vertebrate ancestors and retained as the proteins evolved [1]. Using probabilities for bond formation, the numbers of α2-macroglobulin covalent states is estimated and discussed. The 12 α2-macroglobulin disulfide bonds ranged from a mean of 33 to 92% formed or oxidized in eight healthy human donors (3 male, 5 female, 18–48 years old) (Figure 1) [2]. A protein containing n disulfide bonds, where the bonds are either formed or broken, has 2n possible disulfide-bonded states.
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