geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase


, : Oligomerization-dependent changes in the thermodynamic properties of the TPR-MET receptor tyrosine kinase. Biochemistry 43(32): 10570-8

Although oligomerization of receptor tyrosine kinases (RTKs) is necessary for receptor activation and signaling, a quantitative understanding of how oligomerization mediates these critical processes does not exist. We present a comparative thermodynamic analysis of functionally active dimeric and functionally inactive monomeric soluble analogues of the c-MET RTK, which clearly reveal that oligomerization regulates the binding affinity and binding kinetics of the kinase toward ATP and tyrosine-containing peptide substrates. Thermodynamic binding data for oligomeric c-MET were obtained from the dimeric TPR-MET oncoprotein, a functionally active fusion derivative of the c-MET RTK. This naturally occurring oncoprotein contains the cytoplasmic domain of c-MET fused to a coiled coil dimerization domain from the nuclear pore complex. Comparative data were obtained from a soluble monomeric kinase compromising the c-MET cytoplasmic domain (cytoMET). Significantly, under equilibrium binding conditions, the oligomeric phosphorylated kinase showed a significantly lower dissociation constant (K(d,dimer) = 11 microM) for a tyrosine-containing peptide derived from the C-terminal tail of the c-MET RTK when compared to the phosphorylated monomeric kinase cytoMET (K(d,monomer) = 140 microM). Surprisingly, equilibrium dissociation constants measured for the kinase and ATP were independent of the oligomerization state of the kinase (approximately 10 microM). Stopped-flow analysis of peptide substrate binding showed that the association rate constants (k(2)) differed 2-fold and dissociation rate constants (k(-2)) differed 10-fold when phosphorylated TPR-MET was compared to phosphorylated cytoMET. ATP binding abrogated the differences in k(2) rates observed between the two oligomeric states of the c-MET cytoplasmic domain. These results clearly imply that oligomerization induces important thermodynamic and conformational changes in the substrate binding regions of the c-MET protein and provide quantitative mechanistic insights into the necessary role of oligomerization in RTK activation.

US$19.90

PMID: 15301554

DOI: 10.1021/bi0363275


Other references

Samochowiec, L.; Wójcicki, J., 1966: Therapeutic studies in chronic alcoholic intoxication in white rats. Medicina et Pharmacologia Experimentalis. International Journal of Experimental Medicine 15(5): 530-538

Peters, A., 2011: From the Chief Executive Officer. Australasian Psychiatry 18(5): 472-472

Colcord, M.; Hawes, I.L.; Carabelli, A.J., 1930: Check list of publications on entomology issued by the United States Department of Agriculture through 1927, with subject index. This compilation is arranged in 4 parts: (1) the general series of the Dept.; (2) the publications of the Bureau of Ent.; (3) publications relating to entomology of other bureaus, divisions, and offices of the Dept.; and (4) the subject index.

Akhremitchev, B.B.; Brown, H.; Bemis, J.; Walker, G.C., 1999: Atomic force microscopic imaging of human tissue Elasticity mapping of muscle and bone. Biophysical Journal 76(1 PART 2): A352, Jan

Gunasekaran, S.; Wallace, H.; Snowden, C.; Mikl, D.; England, R.J.A., 2016: Parathyroid ectopia: development of a surgical algorithm based on operative findings. To study the incidence of ectopic parathyroid adenomata from a single surgical series, and to devise a surgical algorithm from the results to follow when an adenoma cannot initially be located. A retrospective review was conducted of prospectively...

Minisola, G.; Dardano, B., 1989: Evaluation of the antalgic activity and tolerability of piroxicam in chronic pain in cervicoarthrosis and lumboarthrosis. A study was carried out to assess the analgesic efficacy and the safety of piroxicam and to compare them with those of a piroxicam derivative, piroxicam beta-cyclodextrin, in chronic pain caused by arthritis of the neck and lower back. The drugs i...

Drexel, H.; Kirchmair, W.; Dienstl, F., 1981: Anaphylactic shock after intravenous chloramphenicol. Mmw, Munchener Medizinische Wochenschrift 123(18): 756-756

Poffenbarger, M.; Fuller, G.M., 1976: Is melatonin a micro tubule inhibitor. The effect of melatonin (5-methoxy-N-acetyltryptamine) on microtubule assembly was assessed by viscometry, cell kinetics and [3H]colchicine binding studies. Melatonin has no effect on the in vitro assembly of bovine brain microtubules. [3H]Colchic...

Ohtake H.; Shinohara M.; Yamamoto F.; Ueno S., 1988: The effect of hyperbaric oxygenation in patients with retinal artery occlusion. We report the good visual effect of hyperbaric therapy on two cases of branch retinal artery occlusion. Although the patients were treated for a relatively long period from onset, final visual acuity improved from 0.05 to 0.5 and from 0.15 to 0.5....

Mordan, L.J.; Toback, F.G., 1984: Growth of kidney epithelial cells in culture: evidence for autocrine control. The factors that stimulate kidney growth in K+-deficient animals are unknown. Cultures of renal epithelial cells (BSC-1 line) were used to study this phenomenon because their growth is accelerated in medium containing a reduced K+ concentration. W...