Biomedical subjects
Publications and source records attributed to T T Wu.
A human lambdaV (Mcg) and a human lambdaII (Vil) myeloma protein have identical sequences in their first hypervariable segments although they differ at 21 positions throughout the variable region. If a different structural gene is responsible for each subgroup, the findings favor insertion of information for the hypervariable or complementarity-determining segments.
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An analysis is made of various predictive methods used to locate alpha-helices and beta-sheets in proteins. The analysis is based on attempts to locate the alpha-helices and beta-sheets in adenylate kinase (ATP:AMP phosphotransferase EC 2.7.4.3) from the sequence without prior knowledge of the x-ray findings. Specification of the beta-sheet breaking and alpha-helix breaking tripeptides, a method independent of the others combined with the best of the other methods would substantially reduce the prediction of nonexistent beta-sheets and to a lesser extent would aid in locating alpha-helices.
Newer data from the x-ray crystallographic studies of tuna heart ferrocytochrome c have increased the number of residues in alpha-helical segments. This provided an objective test of our method of predicting varphi,Psi values for cytochrome c using the sequences of 18 cytochromes c and twenty 20 x 20 tables for the varphi,Psi values of tripeptides in 10 other proteins whose three-dimensional structures were known from x-ray crystallographic studies. Of the 32 residues now considered from x-ray data to be in alpha-helices, 27 had been predicted to be in the alpha-helical domain.
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A 20 x 20 table of tripeptides has been compiled that may be used to locate beta-sheet breaking and alpha-helix breaking residues in proteins. It is based on the definition of an alpha-helical and a beta-sheet domain on the (varphi, Psi) map based on the occurrences of alpha-helices and beta-sheets in 12 known proteins whose sequence and three-dimensional structure have been determined. Each entry in the 20 x 20 table lists three numbers, the frequency of occurrences of the middle amino acid (n) in relation to its nearest neighbors (n - 1) and (n + 1) in the alpha-helical domain, the beta-sheet domain and outside these regions. The regions between two beta-sheet-breaking residues would be permissively beta-sheet regions. The sequence of concanavalin A has been examined in this manner and of the 13 beta-strands defined by x-ray crystallography, 10 were in agreement with the permissively beta-sheet regions and, in the remaining three, beta-sheet-breaking residues were the third in one, and the third, fourth, and fifth residues in another, and the sixth residue in the third from the beginning of the beta-strands. The findings provide strong support for the role of nearest-neighboring amino acids in determining secondary structure of proteins.
From (varphi,Psi) data for the middle amino acid, n, in the series of tripeptides (n - 1)(n)(n + 1) in six proteins whose three-dimensional structure is known from x-ray studies, (varphi,Psi) values for the residues 2-107 of kappa Bence Jones proteins and immunoglobulin light chains were computed. It was assumed that all residues except those in the hypervariable regions 24-34, 50-56, and 89-97, were involved essentially in three-dimensional structure, and hence, their (varphi,Psi) angles would mostly be those best satisfying all kappa tri- and constituent di-peptides that occur at those positions. A set of criteria for selecting and averaging (varphi,Psi) angles is given. In the hypervariable regions, which are presumed to be involved in site complementarity, the (varphi,Psi) angles were selected for a single Bence Jones protein Ag. The three-dimensional models, constructed from the computed (varphi,Psi) values by hand and by display computer were very similar, and residues 23 and 88 were sufficiently close for the disulfide bond to form.
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From a consideration of (varphi, Psi) values of the amino acids of myoglobin, lysozyme, the alpha and beta chains of horse oxyhemoglobin, tosyl-alpha-chymotrypsin, and carboxypeptidase A, an empirical procedure of predicting whether amino-acid residues in proteins are in a non-helical or may be in a helical conformation has been developed. The conformation of an amino acid at any position n is considered to be influenced by its nearest neighbors (the amino acids at positions n + 1 and n - 1), and the (varphi, Psi) values of the middle amino acid n for the various tripeptide sequences in the known proteins are tabulated. If helical, the (varphi, Psi) values are plotted to define a helical (varphi, Psi) domain. A 20 x 20 table for all tripeptides (n - 1)-(n)-(n + 1) taken sequentially for the entire chain was constructed; it lists the number of instances in which helical and non-helical conformations for the amino acids at position n were found. Certain sequences are found to be associated exclusively with non-helical and others exclusively with helical conformations, whereas many sequences may be either helical or non-helical. The distribution of non-helical residues serves to limit stretches of permissively helical regions; these are then further examined by the helical wheel method. As applied to cytochrome c from 18 species, the only permissively helical segment found was the stretch 91-101 near the C-terminus. For the variable regions of three light and three heavy chains of immunoglobulins, upper limits of 12 and 17% alpha-helix, respectively, were obtained.
In an attempt to account for antibody specificity and complementarity in terms of structure, human kappa-, human lambda-, and mouse kappa-Bence Jones proteins and light chains are considered as a single population and the variable and constant regions are compared using the sequence data available. Statistical criteria are used in evaluating each position in the sequence as to whether it is essentially invariant or group-specific, subgroup-specific, species-specific, etc. Examination of the invariant residues of the variable and constant regions confirms the existence of a large number of invariant glycines, no invariant valine, lysine, and histidine, and only one invariant leucine and alanine in the variable region, as compared with the absence of invariant glycines and presence of three each of invariant alanine, leucine, and valine and two each of invariant lysine and histidine in the constant region. The unique role of glycine in the variable region is emphasized. Hydrophobicity of the invariant residues of the two regions is also evaluated. A parameter termed variability is defined and plotted against the position for the 107 residues of the variable region. Three stretches of unusually high variability are noted at residues 24-34, 50-56, and 89-97; variations in length have been found in the first and third of these. It is hypothesized that positions 24-34 and 89-97 contain the complementarity-determining residues of the light chain-those which make contact with the antigenic determinant. The heavy chain also has been reported to have a similar region of very high variability which would also participate in forming the antibody-combining site. It is postulated that the information for site complementarity is contained in some extrachromosomal DNA such as an episome and is incorporated by insertion into the DNA of the structural genes for the variable region of short linear sequences of nucleotides. The advantages and disadvantages of this hypothesis are discussed.
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In view of the differences of the X-ray diffraction patterns for DNA fibers at 66 and 92 per cent relative humidities, it is proposed that the secondary structure of DNA consists of two partially intercalated double helices at 92 per cent. Possible biological implications are discussed.