Structure disulfide bonding

Disulfide bond exchange. Disulfide linkages are important in determining protein tertiary structure. Disulfide bond formation and/or exchange may occur during metal-catalyzed oxidation of the cysteine residue. This may lead to protein aggregation due to the formation of intermo-lecular disulfide bonds. In addition to cysteine disulfide bond formation, cysteine is susceptible to oxidation (Fig. 134) (200) (See also discussion on thiol chemistry earlier in this chapter). 

Disulfide bonds These covalent bonds form between Cys residues that are close together in the final conformation of the protein (see Fig. 4) and function to stabilize its three-dimensional structure. Disulfide bonds are really only formed in the oxidizing environment of the endoplasmic reticulum (see Topic A2), and thus are found primarily in extracellular and secreted proteins. 

Disulfide bonds play an important role in maintaining tertiary structure. Disulfide bonds are formed between side chains of two cysteine units by oxidation of their thiol groups (—SH) to form a disulfide bond (Section 8.6B). Treatment of a disulfide bond with... 

Van Etten, R.L., Davidson, R., Stevis, P.E., MacArthur, H., and Moore D.L., 1991, Covalent structure, disulfide bonding, and identification of reactive surface and active site residues of human prostatic acid phosphatase./. Biol. Chem. 266 2313-2319. 

The second application of the CFTI approach described here involves calculations of the free energy differences between conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution [9, 10]. DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen, where D-Pen is the D isomer of /3,/3-dimethylcysteine) and other opioids are an interesting class of biologically active peptides which exhibit a strong correlation between conformation and affinity and selectivity for different receptors. The cyclic form of DPDPE contains a disulfide bond constraint, and is a highly specific S opioid [llj. Our simulations provide information on the cost of pre-organizing the linear peptide from its stable solution structure to a cyclic-like precursor for disulfide bond formation. Such... 

The Cyc conformer represents the structure adopted by the linear peptide prior to disulfide bond formation, while the two /3-turns are representative stable structures of linear DPDPE. The free energy differences of 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. 

Note A molecular dynamics sim u lation cannot overcome con -strain is imposed by covalent bonds, such as disulfide bonds and rings. Check that such constraints are acceptable. Search other possible structures in separate simulations. 

The shape of a large protein is influenced by many factors including of course Its primary and secondary structure The disulfide bond shown m Figure 27 18 links Cys 138 of carboxypeptidase A to Cys 161 and contributes to the tertiary structure Car boxypeptidase A contains a Zn " ion which is essential to the catalytic activity of the enzyme and its presence influences the tertiary structure The Zn ion lies near the cen ter of the enzyme where it is coordinated to the imidazole nitrogens of two histidine residues (His 69 His 196) and to the carboxylate side chain of Glu 72... 

The primary structure of a peptide is given by its ammo acid sequence plus any disulfide bonds between two cysteine residues The primary structure is determined by a systematic approach m which the protein is cleaved to smaller fragments even individual ammo acids The smaller fragments are sequenced and the mam sequence deduced by finding regions of overlap among the smaller peptides... 

A prior distribution for sequence profiles can be derived from mixtures of Dirichlet distributions [16,51-54]. The idea is simple Each position in a multiple alignment represents one of a limited number of possible distributions that reflect the important physical forces that determine protein structure and function. In certain core positions, we expect to get a distribution restricted to Val, He, Met, and Leu. Other core positions may include these amino acids plus the large hydrophobic aromatic amino acids Phe and Trp. There will also be positions that are completely conserved, including catalytic residues (often Lys, GIu, Asp, Arg, Ser, and other polar amino acids) and Gly and Pro residues that are important in achieving certain backbone conformations in coil regions. Cys residues that form disulfide bonds or coordinate metal ions are also usually well conserved. 

CH2SH + 1/2 O2 -CH2-S-S-CH2 + H2O Disulfide bonds form between the side chains of two cysfeine residues. Two SH groups from cysteine residues, which may be in different parts of the amino acid sequence but adjacent in the three-dimensional structure, are oxidized to form one S-S (disulfide) group. 

Figure 6.6 Schematic diagram of the structure of the enzyme lysozyme which folds into two domains. One domain is essentially a-helical whereas the second domain comprises a three stranded antiparallel p sheet and two a helices. There are three disulfide bonds (green), two in the a-helical domain and one in the second domain.

Disulfide bonds in proteins are generally stable and nonreactive, acting like bolts in the structure. However, oxidized DsbA is less stable than the reduced form and its disulfide bond is very reactive. DsbA is thus a strong... 

Figure 6.8 Schematic diagram of the enzyme DsbA which catalyzes disulfide bond formation and rearrangement. The enzyme is folded into two domains, one domain comprising five a helices (green) and a second domain which has a structure similar to the disulfide-containing redox protein thioredoxin (violet). The N-terminal extension (blue) is not present in thioredoxin. (Adapted from J.L. Martin et al.. Nature 365 464-468, 1993.)...

The basic structure of all immunoglobulin (Ig) molecules comprises two identical light chains and two identical heavy chains linked together by disulfide bonds (Figure IS.2a). There are two different classes, or isotypes, of light chains, X and k, but there is no known functional distinction between them. Heavy chains, by contrast, have five different isotypes that divide the immunoglobulins into different functional classes IgG, IgM, IgA, IgD, and IgE, each with different effector properties in the elimination of antigen... 

Figure 15.17 The three-dimensional structure of an intact IgG. Hinge regions connecting the Fab arms with the Fc stem are relatively flexible, despite the presence of disulfide bonds in this region linking the heavy and light chains. Carbohydrate residues that bridge the two Ch2 domains are not shown. (Courtesy of A. McPherson and L. Harris, Nature 360 369-372, 1992, by copyright permission of Macmillan Magazines Limited.)...

Figure 15.18 (a) Schematic representation of the path of the polypeptide chain in the structure of the class I MHC protein HLA-A2. Disulfide bonds are indicated as two connected spheres. The molecule is shown with the membrane proximal immunoglobulin-like domains (a3 and Pzm) at the bottom and the polymorphic al and a2 domains at the top. 

IgG antibody molecules are composed of two light chains and two heavy chains joined together by disulfide bonds. Each light chain has one variable domain and one constant domain, while each heavy chain has one variable and three constant domains. All of the domains have a similar three-dimensional structure known as the immunoglobulin fold. The Fc stem of the molecule is formed by constant domains from each of the heavy chains, while two Fab arms are formed by constant and variable domains from both heavy and light chains. The hinge region between the stem and the arms is flexible and allows the arms to move relative to each other and to the stem. 

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