Folds of the polypeptide chains

Homologous proteins have similar three-dimensional structures. They contain a core region, a scaffold of secondary structure elements, where the folds of the polypeptide chains are very similar. Loop regions that connect the building blocks of the scaffolds can vary considerably both in length and in structure. From a database of known immunoglobulin structures it has, nevertheless, been possible to predict successfully the conformation of hyper-variable loop regions of antibodies of known amino acid sequence. 

X-ray structures are determined at different levels of resolution. At low resolution only the shape of the molecule is obtained, whereas at high resolution most atomic positions can be determined to a high degree of accuracy. At medium resolution the fold of the polypeptide chain is usually correctly revealed as well as the approximate positions of the side chains, including those at the active site. The quality of the final three-dimensional model of the protein depends on the resolution of the x-ray data and on the degree of refinement. In a highly refined structure, with an R value less than 0.20 at a resolution around 2.0 A, the estimated errors in atomic positions are around 0.1 A to 0.2 A, provided the amino acid sequence is known. 

Cluster 1 is a conventional [4Fe-4S] cubane cluster bound near the N-terminus of the molecule as shown in Fig. 13. Within the cluster the Fe-S bonds range from 2.26 to 2.39 A. The cluster is linked to the protein by four cysteine residues with Fe-S distances ranging from 2.21 to 2.35 A, but the distribution of the cysteine residues along the polypeptide chain contrasts markedly with that found, for example, in the ferredoxins as indicated in Section II,B,4 [also see, for example, 41) and references therein]. In the Fepr protein all four cysteine residues (Cys 3, 6, 15, and 21) originate from the N-terminus of the molecule, and the fold of the polypeptide chain in this region is such that it wraps itself tightly around the cluster, yet keeps it near the surface of the molecule. In such a position the cluster is ideally placed to participate in one-electron transfer reactions with other molecules. 

Protein folding Glycosylation can effect local protein secondary structure and help direct folding of the polypeptide chain... 

Fig. 29. EF hand showing the folding of the protein around sites X, Y, Z, - Y, -X, -Z. (a) The basic diagram of hands, (b) the identification of six locations of ligands (see Table XII for details of the symbols), (c) the octahedron built from (b), (d) the types of atoms found in each location (see Table XII), and (e) the direction of folding of the polypeptide chain around the calcium ion.

Correct answer = E. The correct folding of a pro tein is guided by specific interactions among the side chains of the amino acid residues of a polypeptide chain. The two cysteine residues that react to form the disulfide bond may be a great distance apart in the primary structure (or on sep arate polypeptides), but are brought into close proximity by the three-dimensional folding of the polypeptide chain. Denaturation may either be reversible or irreversible. Quaternary structure requires more than one polypeptide chain. These chains associate through noncovalent interactions. 

The structures of several dehydrogenases have now been solved. The work on these has been reviewed in depth in the literature, as have their physical and kinetic properties.1,9,10 Some generalizations can be made. As was discussed in Chapter 1, section D6, the subunits may be divided into two domains a catalytic domain, which can be quite variable in structure, and a nucleotide-binding domain, which is formed from a similar overall folding of the polypeptide chain for all the dehydrogenases. The detailed geometry of the nucleotide-binding... 

Further association of domains results in the formation of the protein s tertiary structure—the overall folding of the polypeptide chain in three dimensions. Finally fully folded protein subunits can pack together to form quaternary structures. 

Fig. 5. The folding of the polypeptide chain into an a-helix. (a) Model of an a-helix with only the Ca atoms along the backbone shown (b) in the a-helix the CO group of residue n is hydrogen bonded to the NH group on residue (n + 4) (c) cross-sectional view of an a-helix showing the positions of the side-chains (R groups) of the amino acids on the outside of the helix.

Fig. 6. The folding of the polypeptide chain in a p-pleated sheet, (a) Hydrogen bonding between two sections of a polypeptide chain forming a p-pleated sheet (b) a side-view of one of the polypeptide chains in a /3-pleated sheet showing the side-chains (R groups) attached to the Ca atoms protruding above and below the sheet (c) because the polypeptide chain has polarity either parallel or antiparallel /3-pleated sheets can form.

The complete pattern of folding of the polypeptide chain of a protein, whether regular or irregular, is called the tertiary structure. The tertiary structure of any protein is the sum of many forces and structural elements, many of which are the result of interactions between the side chain groups of amino acids in the protein. Some of these interactions are described below. 

The determination of the secondary and tertiary structure—that is, the details of the three-dimensional folding of the polypeptide chain of a protein at high resolution—relies on one of two powerful techniques x-ray diffraction analysis of protein crystals and multidimensional high-field nuclear magnetic resonance (NMR) spectroscopy. Both methods provide very detailed structural in-... 

In globular proteins, the folding of the polypeptide chain is such that the amino acids with nonpolar side chains are assembled in the interior to form a hydro-phobic core, whereas the amino acids with polar and charged side chains tend to be at the surface to interact with the (aqueous) solvent. This oil-drop-like distribution of hydrophilic and hydrophobic amino acids is of importance for the functionality and stability of a protein because pK values of acidic and basic side chains can be shifted in nonpolar environment by several units, and internal hydrogen bonds are strengthened because the donors and acceptors do not have to compete with water molecules [133, 134J. 

Fig. 19.5. Schematic diagram of the three-dimensional folding of the polypeptide chain (Fig. 19.2) of ribonuclease Tj in a complex with the specific inhibitor guanosine-2 -phosphate [594] S-S, disulfide bridges thick arrows indicate / -strands...

F g. 5.6 Arrestin is an elongated molecule. The fold of the polypeptide chains is shown. The crystal structure of bovine arrestin comprises two domains of antiparallel [fsheets connected through a hirrge r on and one short a-helix on the back of the amino-terminai fold. The region where arrestin binds to the phosphorylated light-activated rhodopsin is located at the N-terminal domain, on top. This is also supported by binding studies with N-terminally truncated arrestin. (This ribbon model of arrestin is reproduced with permission of the authors and Cell... 

The identification of the amino acids at the active center is very important if the mechanism of the enzymic reaction is to be understood, but unambiguous evidence concerning the nature of such acids is extremely diflScult to obtain. (It should be emphasized that the amino acids of the active site need not be close to one another in the amino acid sequence of the protein, as folding of the polypeptide chains can bring them together.) For catalytic activity, many enzymes require a non-protein ion or molecule, bound to (or in close association with) the enzyme—protein. The nature of this prosthetic group, or coenzyme, must be investigated in order that the enzymic action may be fully understood. 

Proteins are the workhorses of biochemistry, participating in essentially all cellular processes. Protein structure can be described at four levels. The primary structure refers to the amino acid sequence. The secondary structure refers to the conformation adopted by local regions of the polypeptide chain. Tertiary structure describes the overall folding of the polypeptide chain. Finally, quaternary structure refers to the specific association of multiple polypeptide chains to form multisubunit complexes. 

Mandelbrot [23] has shown that the most random type of height distribution to be expected on earth is of a fractal type. The same should be true for a value distribution in the v-dimensional sequence space. Such a fractal distribution is highly connective, that is, anything but uncorrelated. Moreover, we know that functional efficiency is clustered around certain sequences. The functional efficiency of an enzyme depends on the correct spatial arrangement of certain amino acid residues that comprise the active center this is achieved by three-dimensional folding of the polypeptide chain [24]. Hence there exists a correlation ... 

Understanding of protein structure and function has been greatly enhanced by X-ray crystallography. At low resolution (4-6 Angstrom), the electron density map reveals the folding of the polypeptide chain, but few other structural details. At 3.0 A, it is possible, in favourable cases, to resolve amino acid chains, while at 2.5 A the positions of atoms may often be given with an accuracy of 0.4 A. In order to locate atoms to 0.2 A, a resolution of about 1.9 A and very well ordered crystals are necessary.3 -32... 

Fig. 19.5 The myoglobin molecule (a) ihe folding of the polypeptide chain about the heme group (represented by the disk) (b) close-up view of the heme environment. [Modified from Kendrew, J. C. Dickerson, R. E. Strandberg, B. E. Han. R. G. Davies. D. R. Phillips, D. C. Shore, V. C. Nature I960, 185, 422-427. Reproduced with permission.]...

Note added in proof Further inferences have been drawn, as a result of the analysis of a three-dimensional PATTEESON-diagram, concerning the orientation and folding of the polypeptide chains within the layer structure of the hemoglobin molecule. See M. F. Perutz, An X-ray Study of Methemoglobin. II. Proc.Roy. Soc. (London) A 19S, 474 (1949). 

Tertiary structure involves the intramolecular folding of the polypeptide chain into a compact three-dimensional structure with a specific shape. This structure is maintained by electrovalent linkages, hydrogen bonds, disulfide bridges, van der Waals forces, and hydrophobic interactions. Hydrophobic interactions are considered to be a major force in maintaining the unique tertiary structure of proteins. 

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