Protein structure sheets

Beta strands can also combine into mixed P sheets with some P strand pairs parallel and some antiparallel. There is a strong bias against mixed P sheets only about 20% of the strands inside the p sheets of known protein structures have parallel bonding on one side and antiparallel bonding on the other. Figure 2.7 illustrates how the hydrogen bonds between the p strands are arranged in a mixed P sheet. 

As they occur in known protein structures, almost all P sheets—parallel, antiparallel, and mixed—have twisted strands. This twist always has the same handedness as that shown in Figure 2.7, which is defined as a right-handed twist. 

This motif is called a beta-alpha-beta motif (Figure 2.17) and is found as part of almost every protein structure that has a parallel p sheet. For example, the molecule shown in Figure 2.10b, triosephosphate isomerase, is entirely built up by repeated combinations of this motif, where two successive motifs share one p strand. Alternatively, it can be regarded as being built up from four consecutive p-a-p-a motifs. 

Figure 2.17 Two adjacent parallel p strands are usually connected by an a helix from the C-termlnus of strand 1 to the N-termlnus of strand 2. Most protein structures that contain parallel p sheets are built up from combinations of such p-a-P motifs. Beta strands are red, and a helices are yellow. Arrows represent P strands, and cylinders represent helices, (a) Schematic diagram of the path of the main chain, (b) Topological diagrams of the P-a-P motif.

On the basis of simple considerations of connected motifs, Michael Leviff and Cyrus Chothia of the MRC Laboratory of Molecular Biology derived a taxonomy of protein structures and have classified domain structures into three main groups a domains, p domains, and a/p domains. In ct structures the core is built up exclusively from a helices (see Figure 2.9) in p structures the core comprises antiparallel p sheets and are usually two P sheets packed... 

Figure 5.10 Idealized diagrams of the Greek key motif. This motif is formed when one of the connections of four antiparallel fi strands is not a hairpin connection. The motif occurs when strand number n is connected to strand + 3 (a) or - 3 (b) instead of -r 1 or - 1 in an eight-stranded antiparallel P sheet or barrel. The two different possible connections give two different hands of the Greek key motif. In all protein structures known so far only the hand shown in (a) has been observed.

Cohen, F.E., Sternberg, M.J.E., Taylor, W.R. Analysis of the tertiary structure of protein p-sheet sandwiches. 

For each fold one searches for the best alignment of the target sequence that would be compatible with the fold the core should comprise hydrophobic residues and polar residues should be on the outside, predicted helical and strand regions should be aligned to corresponding secondary structure elements in the fold, and so on. In order to match a sequence alignment to a fold, Eisenberg developed a rapid method called the 3D profile method. The environment of each residue position in the known 3D structure is characterized on the basis of three properties (1) the area of the side chain that is buried by other protein atoms, (2) the fraction of side chain area that is covered by polar atoms, and (3) the secondary stmcture, which is classified in three states helix, sheet, and coil. The residue positions are rather arbitrarily divided into six classes by properties 1 and 2, which in combination with property 3 yields 18 environmental classes. This classification of environments enables a protein structure to be coded by a sequence in an 18-letter alphabet, in which each letter represents the environmental class of a residue position. 

These results indicate that is it possible to change the fold of a protein by changing a restricted set of residues. They also confirm the validity of the rules for stability of helical folds that have been obtained by analysis of experimentally determined protein structures. One obvious impliction of this work is that it might be possible, by just changing a few residues in Janus, to design a mutant that flip-flops between a helical and p sheet structures. Such a polypeptide would be a very interesting model system for prions and other amyloid proteins. 

The second major class of protein structures contains structures based around parallel or mixed j8-sheets. Parallel /3-sheet arrays, as previously discussed, distribute hydrophobic side chains on both sides of the sheet. This means that neither side of parallel /3-sheets can be exposed to solvent. Parallel /3-sheets are thus typically found as core structures in proteins, with little access to solvent. 

The immunoglobulin structure in Figure 6.45 represents the confluence of all the details of protein structure that have been thus far discussed. As for all proteins, the primary structure determines other aspects of structure. There are numerous elements of secondary structure, including /3-sheets and tight turns. The tertiary structure consists of 12 distinct domains, and the protein adopts a heterotetrameric quaternary structure. To make matters more interesting, both intrasubunit and intersubunit disulfide linkages act to stabilize the discrete domains and to stabilize the tetramer itself. 

Two of the most common motifs in the hundreds of known protein structures are the so-called a helix and the P sheet. 

Michael reactions and, 895 Beta-keto ester, 851 alkylation of, 859-860 cyclic, 892-893 decarboxylation of, 857, 860 Michael reactions and. 895 pKd of, 852 synthesis of, 892-893 Beta-lactam antibiotics, 824-825 Beta oxidation pathway, 1133-1137 mechanism of, 1133-1136 Beta-pleated sheet (protein), 1038 molecular model of, 1039 secondary protein structure and, 1038-1039 Betaine, 720 Bextra. structure of, 544 BHA, synthesis of, 629 BHT, synthesis of. 629 Bicycloalkane. 129 Bijvoet. J. M., 299 Bimolecular, 363... 

Detailed protein structures have been reported for BPI and CETP. Given the aforementioned similarities within this gene family, these protein structures serve as a likely model for the protein structure of PLTP. CETP and BPI are elongated molecules, shaped like a boomerang. There are two domains with similar folds, and a central beta-sheet domain between these two domains. The molecules contain two lipid-binding sites, one in each domain near the interface of the barrels and the central beta-sheet. 

These are exciting times for peptide based materials. The number of investigators in this field and consequently the number of publications in this area have increased tremendously in recent years. Not since the middle of the past century has there been so much activity focused on the physical properties of peptidic materials. Then, efforts were focused on determination of the fundamental elements that make up protein structures, leading to the discoveries of the a—helix and the (3-sheet. Many years of study followed where the propensities of individual and combinations of amino acids to adopt and stabilize these structures were investigated. Now, this knowledge is being applied to the preparation, assembly, and use of peptide based materials with designed sequences. This volume summarizes recent developments in all these areas. 

Although other secondary protein structures play roles in determining the shapes of proteins, the helix and pleated sheet occur most frequently. A discussion of less common secondary structures is beyond the scope of this text. 

The essential distinction between the approaches used to formulate and evaluate proteins, compared with conventional low molecular weight drugs, lies in the need to maintain several levels of protein structure and the unique chemical and physical properties that these higher-order structures convey. Proteins are condensation polymers of amino acids, joined by peptide bonds. The levels of protein architecture are typically described in terms of the four orders of structure [23,24] depicted in Fig. 2. The primary structure refers to the sequence of amino acids and the location of any disulfide bonds. Secondary structure is derived from the steric relations of amino acid residues that are close to one another. The alpha-helix and beta-pleated sheet are examples of periodic secondary structure. Tertiary... 

These spectra are similar to that of native RNase A at 95°C (not shown). The far-UV spectrum at 95°C indicates a retention of substantial p-sheet secondary structure, but a significant loss of the a-helix conformation as indicated by the decrease of intensity at 222 nm.48 The near-UV spectrum at 95°C indicates a complete collapse of tertiary structure as is seen in molten globule proteins.49 Trace 3 is the sample from trace 2 after cooling the protein to 23°C. Both spectra reveal little recovery of either secondary or tertiary protein structure. 

Due to the ready accessibility of SH2 domains by molecular biology techniques, numerous experimentally determined 3D structures of SH2 domains derived by X-ray crystallography as well as heteronuclear multidimensional NMR spectroscopy are known today. The current version of the protein structure database, accessible to the scientific community by, e.g., the Internet (http //www.rcsb.org/pdb/) contains around 80 entries of SH2 domain structures and complexes thereof. Today, the SH2 domain structures of Hck [62], Src [63-66], Abl [67], Grb2 [68-71], Syp [72], PLCy [73], Fyn [74], SAP [75], Lck [76,77], the C- and N-terminal SH2 domain ofp85a [78-80], and of the tandem SH2 domains Syk [81,82], ZAP70 [83,84], and SHP-2 [85] are determined. All SH2 domains display a conserved 3D structure as can be expected from multiple sequence alignments (Fig. 4). The common structural fold consists of a central three-stranded antiparallel ft sheet that is occasionally extended by one to three additional short strands (Fig. 5). This central ft sheet forms the spine of the domain which is flanked on both sides by regular a helices [49, 50,60]. 

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