1ryo: Difference between revisions
New page: left|200px<br /> <applet load="1ryo" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ryo, resolution 1.20Å" /> '''Human serum transfe... |
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[[Image:1ryo.gif|left|200px]]<br /> | [[Image:1ryo.gif|left|200px]]<br /><applet load="1ryo" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1ryo, resolution 1.20Å" /> | caption="1ryo, resolution 1.20Å" /> | ||
'''Human serum transferrin, N-lobe bound with oxalate'''<br /> | '''Human serum transferrin, N-lobe bound with oxalate'''<br /> | ||
==Overview== | ==Overview== | ||
A unique feature of the mechanism of iron binding to the transferrin (TF) | A unique feature of the mechanism of iron binding to the transferrin (TF) family is the synergistic relationship between metal binding and anion binding. Little or no iron will bind to the protein without concomitant binding of an anion, physiologically identified as carbonate. Substitution of oxalate for carbonate produces no significant changes in polypeptide folding or domain orientation in the N-lobe of human serum TF (hTF) as revealed by our 1.2A structure. The oxalate is able to bind to the iron in a symmetric bidentate fashion, which, combined with the low pK(a) of the oxalate anion, makes iron displacement more difficult as documented by both iron release kinetic and equilibrium data. Characterization of an N-lobe in which the arginine at position 124 is mutated to alanine reveals that the stabilizing effect of oxalate is even greater in this mutant and nearly cancels the destabilizing effect of the mutation. Importantly, incorporation of oxalate as the synergistic anion appears to completely inhibit removal of iron from recombinant full-length hTF by HeLa S(3) cells, strongly indicating that oxalate also replaces carbonate in the C-lobe to form a stable complex. Kinetic studies confirm this claim. The combination of structural and functional data provides a coherent delineation of the effect of oxalate binding on hTF and rationalizes the results of many previous studies. In the context of iron uptake by cells, substitution of carbonate by oxalate effectively locks the iron into each lobe of hTF, thereby interfering with normal iron metabolism. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1RYO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with OXL and FE as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 1RYO is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=OXL:'>OXL</scene> and <scene name='pdbligand=FE:'>FE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RYO OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Adams, T | [[Category: Adams, T E.]] | ||
[[Category: Briggs, S | [[Category: Briggs, S K.]] | ||
[[Category: Everse, S | [[Category: Everse, S J.]] | ||
[[Category: Halbrooks, P | [[Category: Halbrooks, P J.]] | ||
[[Category: Mason, A | [[Category: Mason, A B.]] | ||
[[Category: FE]] | [[Category: FE]] | ||
[[Category: OXL]] | [[Category: OXL]] | ||
[[Category: iron transport]] | [[Category: iron transport]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:55:57 2008'' | ||
Revision as of 15:55, 21 February 2008
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Human serum transferrin, N-lobe bound with oxalate
OverviewOverview
A unique feature of the mechanism of iron binding to the transferrin (TF) family is the synergistic relationship between metal binding and anion binding. Little or no iron will bind to the protein without concomitant binding of an anion, physiologically identified as carbonate. Substitution of oxalate for carbonate produces no significant changes in polypeptide folding or domain orientation in the N-lobe of human serum TF (hTF) as revealed by our 1.2A structure. The oxalate is able to bind to the iron in a symmetric bidentate fashion, which, combined with the low pK(a) of the oxalate anion, makes iron displacement more difficult as documented by both iron release kinetic and equilibrium data. Characterization of an N-lobe in which the arginine at position 124 is mutated to alanine reveals that the stabilizing effect of oxalate is even greater in this mutant and nearly cancels the destabilizing effect of the mutation. Importantly, incorporation of oxalate as the synergistic anion appears to completely inhibit removal of iron from recombinant full-length hTF by HeLa S(3) cells, strongly indicating that oxalate also replaces carbonate in the C-lobe to form a stable complex. Kinetic studies confirm this claim. The combination of structural and functional data provides a coherent delineation of the effect of oxalate binding on hTF and rationalizes the results of many previous studies. In the context of iron uptake by cells, substitution of carbonate by oxalate effectively locks the iron into each lobe of hTF, thereby interfering with normal iron metabolism.
DiseaseDisease
Known diseases associated with this structure: Atransferrinemia OMIM:[190000], Iron deficiency anemia, susceptibility to OMIM:[190000]
About this StructureAbout this Structure
1RYO is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
The oxalate effect on release of iron from human serum transferrin explained., Halbrooks PJ, Mason AB, Adams TE, Briggs SK, Everse SJ, J Mol Biol. 2004 May 21;339(1):217-26. PMID:15123433
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