Protein structure and function, from a colloidal to a molecular view

Scheraga, Harold A.

doi:10.1007/bf02913964

Cited by 73 publications

(25 citation statements)

References 376 publications

(281 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The general methods used (9,10) are based on the program ECEPP (empirical conformational energy for polypeptides and proteins) (11) and have been used successfully to compute the allowed conformations of the naturally occurring amino acids (12), short oligopeptides (13), and long, constrained oligopeptides (14,15). These methods have been extended to computing the preferred conformations for long, unconstrained polypeptides (6,16,17).…”

Section: Methodsmentioning

confidence: 99%

Structural effects of substitutions on the p21 proteins.

Pincus¹,

Brandt‐Rauf²

1985

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The conformational effects of different amino acid substitutions (lysine, serine, proline, and D-valine) for glycine at position 12 in the p21 oncogene-encoded proteins have been investigated by using conformational energy calculations. The normal cellular gene codes for a glycine at position 12 in the amino acid sequence, in the middle of a hydrophobic p21-(6-15)-decapepetide from Leu-6 to Gly-15. Mutations that cause amino acid substitutions for Gly-12 result in a protein product that produces malignant transformation of cells. We now find that not only are the preferred structures for the lysine-and serine-containing peptides more restricted and more helical than those for the glycine-containing peptide, but the lowest-energy structure for each substituted peptide is exactly the same as that previously found for the peptide with Val-12, suggesting the existence of a "malignancy-causing" conformation. None of the preferred conformations for the valine-, lysine-, and serine-containing peptides contain chain reversals at positions 11 and 12. However, we find that proline, unlike these residues but like glycine, at position 12 causes helix termination at positions 11 and 12, a result that suggests that the p21 protein product with proline at position 12 may exhibit lowered transforming potential, in agreement with the results of recent genetic recombination experiments.Human oncogenes in the ras family are homologous to a normal cellular protooncogene that codes for a normal protein product of Mr 21,000 (p21 protein), and several of them such as the EJ bladder carcinoma oncogene (1, 2) differ from it in only the 12th coding triplet, which in the protooncogene is GGC, the codon for glycine (1,2). Amino acid substitutions at position 12 in the p21 protein encoded by human ras oncogenes are known to result in abnormal cellular control and ultimately to cause malignant transformation of cells (1-3).The sequence of the first 20 amino acids (1, 2) of the p21 protein encoded by the protooncogene is:Val-Gly-Lys-Ser-Ala-Leu-Thr.Malignant transformation of cells occurs when the glycine at position 12 is replaced by a variety of amino acids (1, 2, 4, 5).This Gly-12 occurs in the middle of a long sequence (the transforming region) of 10 hydrophobic or nonpolar amino acid residues, the only such sequence in the p21 proteins.We have shown previously that glycine at position 12 shows a marked preference for the D* (conformations are explained in the legend to Table 1) conformation that is inaccessible to all naturally occurring L-amino acids (6-8). This result suggested to us that substitution of any other amino acid for glycine at position 12 would result in a mandatory change in chain conformation in the region of residue 12 that may result in malignant transformation (6-8).We also found that, for the "normal" p21 protein, a slightly higher energy conformation existed that was identical to the lowest energy conformer for the transforming p21 protein with valine at position 12 in which the chain reversal (CD*) conform...

show abstract

Section: Methodsmentioning

confidence: 99%

Structural effects of substitutions on the p21 proteins.

Pincus¹,

Brandt‐Rauf²

1985

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…These experiments indicated that it should be possible to calculate the three-dimensional structure of a protein from its amino acid sequence. Many investigators have attempted to carry out such calculations, but until now none has been completely successful; however, considerable progress has been made (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Calculation of Protein Conformation by the Build-up Procedure. Application to Bovine Pancreatic Trypsin Inhibitor Using Limited Simulated Nuclear Magnetic Resonance Data

Vásquez

Scheraga

1988

Journal of Biomolecular Structure and Dynamics

Self Cite

View full text Add to dashboard Cite

Low-energy conformations of a set of tetrapeptides derived from the small protein bovine pancreatic trypsin inhibitor (BPTI) were generated by a build-up procedure from the low-energy conformations of single amino acid residues. At each stage, various-size fragments were built up from all combinations of smaller ones, the total energies were then minimized, and the low-energy conformations were retained for the next stage. The energies of the tetrapeptides were re-ordered by including the effects of hydration. No information other than the amino acid sequence was used to obtain the low-energy conformations of the hydrated tetrapeptides. The latter were then supplemented with a limited set of simulated NMR distance information, derived from the X-ray structure of BPTI, to provide a basis for building the rest of the whole protein molecule by the same procedure. A total of 189 upper bounds, plus 12 pairs of upper and lower bounds pertaining to the location of the three disulfide bonds in this molecule, were used. Four sets of conformations of the entire molecule were generated by utilizing different combinations of smaller fragments. It was possible to obtain low-energy conformations with small rms deviations, 1.1 to 1.4 A for the alpha-carbons, from the structure derived by X-ray diffraction. The average deviations of the backbone dihedral angles were also low, viz. 23 degrees to 26 degrees.

show abstract

“…The general methods used are based on the program ECEPP (empirical conformational energy for polypeptides program) (13). This approach has been successfully used to compute the allowed conformations of the naturally occurring amino acids (14), short oligopeptides (15), long constrained oligopeptides (16,17), and long unconstrained polypeptides (18,19), including other oncogeneencoded protein sequences such as from ras (20)(21)(22)(23)(24) and myc, fos, and jun (25).…”

Section: Methodsmentioning

confidence: 99%

Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function.

Brandt‐Rauf

Rackovsky

Pincus

1990

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The human homologue of the neu oncogene is frequently found in human tumors. Certain amino acid substitutions at position 664 in the transmembrane domain of the neu oncogene-encoded p185 protein product are known to cause malignant transformation of cells. Using conformational energy analysis based on ECEPP (empirical conformational energies for polypeptides program), we have previously determined the preferred three-dimensional structures for the transmembrane domain of the p185 protein with a transforming (glutamic acid) and a nontransforming (valine) substitution at the critical position 664 and found that the global nimumenergy conformation of this region in the nontransforming protein contains a sharp bend, whereas the global minimumenergy conformation for this region from the transforming protein is entirely a-helical. We now demonstrate that this result holds for other known nontransforming (glycine, histidine, tyrosine, and lysine) and transforming (glutamine) substitutions at position 664. Furthermore, a simple statistical thermodynamic analysis of the results indicates that 85% of each of the nontransforming sequences exist with the bend at positions 664 and 665, while =90% of each of the transforming sequences exist as an a-helix. About 9% of the nontransforming sequences exist as the a-helix. These results suggest that if the intracellular concentration of the normal protein is increased at least 10-fold, thereby increasing the a-helical form by this factor, cell transformation should result. This conclusion is directly supported by genetic experiments in which this level of overexpression of the normal protein was achieved with attendant cell transformation.The neu oncogene was originally identified in nitrosoureainduced neuroblastomas of the rat (1, 2). The human homologue of the neu gene, which is also termed c-erbB2 or HER2, has since been identified in advanced human mammary carcinomas (3, 4) and in other human cancers of glandular origin (5-7). The neu gene encodes a protein of 185 kDa (p185), which shares extensive homology with the epidermal growth factor receptor (8) and similarly has three principal domains: an extracellular receptor domain, a single transmembrane domain, and an intracellular domain with tyrosine kinase activity (9). It has been hypothesized that activation of p185 results in the stimulation of cytoplasmic tyrosine kinase activity causing signal transduction in the cell (8,10).Transforming neu genes differ from their nontransforming counterparts by selective amino acid substitutions at position 664 in the transmembrane domain of the p185 protein (10). The neu genes encoding glutamine or glutamic acid at position 664 are found to produce cell transformation in vitro with a high degree of efficiency, whereas neu genes encoding valine, histidine, tyrosine, lysine, or glycine at position 664 do not produce cell transformation except at elevated levels of expression (10). Thus, the region around position 664 is important in regulating the activity of the transforming neu...

show abstract

Protein structure and function, from a colloidal to a molecular view

Cited by 73 publications

References 376 publications

Structural effects of substitutions on the p21 proteins.

Structural effects of substitutions on the p21 proteins.

Calculation of Protein Conformation by the Build-up Procedure. Application to Bovine Pancreatic Trypsin Inhibitor Using Limited Simulated Nuclear Magnetic Resonance Data

Correlation of the structure of the transmembrane domain of the neu oncogene-encoded p185 protein with its function.

Contact Info

Product

Resources

About