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D Sahal J Ramachandran Y Fujita-Yamaguchi 《Archives of biochemistry and biophysics》1988,260(1):416-426
The receptors for insulin and insulin-like growth factor (IGF) I are structurally similar transmembrane proteins. Ligand binding to the extracellular domain of the receptor stimulates its cytoplasmic tyrosine protein kinase which phosphorylates its own beta subunit as well as exogenous substrates. It is believed, from several lines of evidence, that tyrosine-specific protein kinases are mediating some or all of the actions of insulin (or IGF-I). In order to gain insights into the substrate specificity of the structurally related insulin and IGF-I receptor kinases, we have studied the action of highly purified receptors isolated from human placental membranes. Present studies using selected tyrosine-containing polymers have revealed: (i) Polymers such as (Y,A,E)n and (Y-A-E)n inhibit beta subunit autophosphorylation and exogenous substrate phosphorylation by autophosphorylated receptors. (ii) Insulin receptor kinase is at least 10 times more sensitive to these inhibitors than IGF-I receptor kinase. (iii) (Y-A-E)n is approximately 8 times more potent an inhibitor than (Y,A,E)n toward both receptors. (iv) While (E4,Y1)n and (E6,A3,Y1)n are good substrates for both receptor kinases, the ratio of phosphate incorporation into the former to the latter is characteristically high (approximately 4) for the IGF-I receptor and low (approximately 1) for the insulin receptor. These results imply that the substrate specificity and enzymatic action of these two receptor kinases are distinct. 相似文献
3.
We have cloned a cDNA coding for the smallest rat neurofilament protein. The cDNA is 861 nucleotides long coding for 287 amino acids from the internal alpha-helical region and the carboxy-terminal tail domain of the neurofilament protein. Comparison of the porcine, mouse and rat neurofilament protein sequences shows that the protein is highly conserved (greater than 93% identity). Blot analysis indicates that the cDNA is derived from a single neurofilament gene that codes for two different poly(A)+ mRNA species. 相似文献
4.
A square matrix of spots (A) was presented in rapid alternation with an uncorrelated matrix (B). If the square arrays are superimposed spatially one sees random incoherent motion. However, incoherent motion was seen only if the outer edges were exactly aligned. If the outline of matrix A is shifted horizontally by 1 degree in relation to B, then the edges are seen to oscillate to and fro. Surprisingly, all the dots in the matrix were seen to 'adhere' to the edges and to move horizontally (Ramachandran, 1981). We then aligned the edges again to produce incoherent motion and superimposed a sine-wave grating on the pattern. If the grating was moved horizontally then all the spots 'adhered' to it and moved horizontally as well. This illusion ('motion capture') was optimal (a) at a 90 degrees spatial phase shift of the grating; (b) at low spatial frequencies (less than 0.5 cycles); and (c) when the grating was alternated in step with the dot patterns. Density modulated gratings were just as effective. We conclude that the unambiguous motion signal derived from the grating is applied spontaneously to the dots as well. 相似文献
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If the collagen triple helix is so built as to have one set of NH ? O hydrogen bonds of the type N3H3(A) ? O2(B), then it is possible to have a linkage between N1H1(B) and O1(A) through the intermediary of a water molecule with an oxygen O leading to the formation of the hydrogen bonds N1(B) ? O and O (A). In the same configuration, another water molecule with an oxygen O can link two earbonyl oxygens of chains A and B forming the hydrogen bonds O O1(A) and O O0 (B). The two water oxygens also become receptors at the same time for CH ? O hydrogen bonds. Thus, the neighboring chains in the triple helix are held together by secondary valence bond linkages occurring regularly sit intervals of about 3 Å along the length of the protofibril. The additional water molecules occur on the periphery of the proto-fibril and will contribute their full share towards stabilizing the structure in the solid state. In solution, they will be disturbed by the medium unless they are protected by long side groups. It appears that this type of two-bonded structure, in which one NH ? O bond is to a water molecule, can explain several observations on the stability and hydrogen exchange properties of collagen itself and related synthetic polypeptides. The nature of the water bonds and their strength are found to be better in the one-bonded structure proposed from Madras than in the one having the coordinates of Rich and Crick. 相似文献
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Molecular structure of polyglycine II 总被引:1,自引:0,他引:1
9.
Anticoagulant activity of synthetic hirudin peptides 总被引:4,自引:0,他引:4
J M Maraganore B Chao M L Joseph J Jablonski K L Ramachandran 《The Journal of biological chemistry》1989,264(15):8692-8698
Synthetic peptides based on the COOH-terminal 21 residues of hirudin were prepared in order to 1) evaluate the role of this segment in hirudin action toward thrombin, 2) define the shortest peptide derivative with anticoagulant activity, and 3) investigate the role of tyrosine sulfation in the peptides' inhibitory activities. A hirudin derivative of 20 amino acids, Hir45-64 (derived from residues 45-64 of the hirudin polypeptide), was found to effect a dose-dependent increase in the activated partial thromboplastin time (APTT) of normal human plasma but to have no measurable inhibitory activity toward thrombin cleavage of a tripeptidyl p-nitroanilide substrate. Anticoagulant activity in hirudin derivatives was comparable in peptides of 20, 16, and 12 residues truncated from the NH2 terminus. Additional truncated peptides prepared by synthesis and carboxypeptidase treatment reveal that the minimal sequence of a hirudin peptide fragment with maximal anticoagulant activity is contained within the sequence: NH2-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-COOH. The 12-residue derivative thus identified was reacted with dicyclohexylcarbodiimide in the presence of sulfuric acid to yield a Tyr-sulfated peptide, S-Hir53-64. By comparison to unsulfated peptide, S-Hir53-64 was found to contain a specific inhibitory activity enhanced by one order of magnitude toward increase in APTT and to effect a dose-dependent increase in thrombin time of normal human plasma to yield a 4-fold increase in thrombin time with 2.5 micrograms/ml peptide using 0.8 units/ml alpha-thrombin. Comparison of S-Hir53-64 to hirudin in thrombin time and APTT assays reveals a 50-fold difference in molar specific activities toward inhibition of thrombin. Comparison of antithrombin activities of S-Hir53-64 using a variety of animal thrombins demonstrates greatest inhibitory activity toward murine, rat, and human enzymes and a 10-fold reduced activity toward bovine thrombin. 相似文献
10.
J H Lee S Maeda K L Angelos S G Kamita C Ramachandran D A Walsh 《Biochemistry》1992,31(43):10616-10625
Active gamma subunit of skeletal muscle phosphorylase kinase has been obtained by expression of the rat soleus cDNA in a baculovirus system. The protein exhibited the expected pH 6.8/8.2 activity ratio of 0.6, and its activity was insensitive to Ca2+ addition, indicating that it was free gamma subunit and not a gamma subunit-calmodulin complex. It was stimulated approximately 2-fold by Ca(2+)-calmodulin addition, demonstrating that it had retained high-affinity calmodulin binding. By site-directed mutagenesis, we have examined the role of six of the amino acids that constitute the consensus ATP binding site of the protein kinase, which in the gamma subunit is represented by the sequence 26Gly.Arg.Gly.Val.Ser.Ser.Val.Val33. Changes were evaluated by the kinetic determination of the dissociation constants of gamma-ATP, gamma-ADP, gamma-AMP.PCP, and gamma-phosphorylase and the maximum catalytic activity. The mutants Ser26-gamma, Ser29-gamma, Phe30-gamma, and Gly31-gamma each exhibited an essentially identical dissociation constant for gamma subunit phosphorylase, indicating that these mutations had not caused a global alteration in the protein structure but were limited to changes in the nucleotide binding site domain. Substitution of either Val33 (by Gly) or Gly28 (by Ser), two of the most conserved residues in all protein kinases, resulted in enzyme with marginally detectable activity. In noted contrast, the Ser26 mutant, which substituted the first glycine of the consensus glycine trio motif, and which is also very highly conserved, retained at least 25% of the enzymatic activity. The Gly31 substitution, which restored a glycine to a position characteristic for most protein kinases, had little overall effect upon the maximum rate of catalysis. Restoration of Ser30 to the more typical phenylalanine, which is present in most protein kinases, had minimal effect on catalysis. These data provide the first direct evaluation of the roles that different residues play within this consensus glycine trio/valine motif of the protein kinases, which up to now have only been surmised to be of importance because of their conservation. Two unexpected findings are that for one residue that is very conserved (Gly26) there is some flexibility of substitution not apparent from the evolutionary conservation and that a second quite conserved residue in protein kinases (equivalent to Gly at position 31) does not produce a protein optimized for nucleotide binding. 相似文献