2a0q
From Proteopedia
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'''Structure of thrombin in 400 mM potassium chloride''' | '''Structure of thrombin in 400 mM potassium chloride''' | ||
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[[Category: Pineda, A O.]] | [[Category: Pineda, A O.]] | ||
[[Category: Tsopanoglou, N E.]] | [[Category: Tsopanoglou, N E.]] | ||
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Revision as of 15:27, 3 May 2008
Structure of thrombin in 400 mM potassium chloride
Contents |
Overview
Previous studies have suggested that thrombin interacts with integrins in endothelial cells through its RGD (Arg-187, Gly-188, Asp-189) sequence. All existing crystal structures of thrombin show that most of this sequence is buried under the 220-loop and therefore interaction via RGD implies either partial unfolding of the enzyme or its proteolytic digestion. Here, we demonstrate that surface-absorbed thrombin promotes attachment and migration of endothelial cells through interaction with alpha(v)beta(3) and alpha(5)beta(1) integrins. Using site-directed mutants of thrombin we prove that this effect is mediated by the RGD sequence and does not require catalytic activity. The effect is abrogated when residues of the RGD sequence are mutated to Ala and is not observed with proteases like trypsin and tissue-type plasminogen activator, unless the RGD sequence is introduced at position 187-189. The potent inhibitor hirudin does not abrogate the effect, suggesting that thrombin functions through its RGD sequence in a non-canonical conformation. A 1.9-Angstroms resolution crystal structure of free thrombin grown in the presence of high salt (400 mm KCl) shows two molecules in the asymmetric unit, one of which assumes an unprecedented conformation with the autolysis loop shifted 20 Angstroms away from its canonical position, the 220-loop entirely disordered, and the RGD sequence exposed to the solvent.
Disease
Known disease associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
2A0Q is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Thrombin functions through its RGD sequence in a non-canonical conformation., Papaconstantinou ME, Carrell CJ, Pineda AO, Bobofchak KM, Mathews FS, Flordellis CS, Maragoudakis ME, Tsopanoglou NE, Di Cera E, J Biol Chem. 2005 Aug 19;280(33):29393-6. Epub 2005 Jul 5. PMID:15998637 Page seeded by OCA on Sat May 3 18:27:49 2008
