Corticosteroid-binding globulin: Difference between revisions
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< | <StructureSection load='2V95' size='450' side='right' scene='' caption='Cartoon representation of corticosteroid-binding globulin complex with cortisol, [[2v95]]'> | ||
[[Image:2v95.png|left|200px|thumb|Crystal Structure of corticosteroid-binding globulin complex with cortisol, [[2v95]]]] | |||
==Introduction== | ==Introduction== | ||
Corticosteroid-binding globulin (CBG) is a blood plasma protein 50 to 60 kDa in size <ref>PMID:13395526 </ref>,<ref>PMID:7074030 </ref>. Although it is a member of the serine protease inhibitor (SERPIN) structural family, it does not have any known intrinsic serine protease inhibitor activity <ref>PMID:3143075 </ref>. Its physiological function is conventionally thought to be the transport of the weakly water-soluble hormone, cortisol, throughout the circulation <ref>PMID:13395526 </ref>,<ref>PMID:7074030 </ref>. Structural studies of native rat CBG <ref>PMID:17644521 </ref> and a cleaved human CBG-antitrypsin chimera <ref>PMID:18513745 </ref> have corroborated earlier biochemical studies showing that cortisol binds to CBG with a one-to-one stoichiometry. Additionally, CBG is believed to buffer the concentration of free cortisol in the blood, keeping the level constant despite its pulsatile secretion pattern <ref>PMID:9751481 </ref>. CBG is also thought to participate in the stress response by releasing cortisol specifically at inflammatory sites upon cleavage by human neutrophil elastase between residues 344 and 345<ref>PMID:3143075 </ref>. | '''Corticosteroid-binding globulin''' (CBG) is a blood plasma protein 50 to 60 kDa in size <ref>PMID:13395526 </ref>,<ref>PMID:7074030 </ref>. Although it is a member of the serine protease inhibitor (SERPIN) structural family, it does not have any known intrinsic serine protease inhibitor activity <ref>PMID:3143075 </ref>. Its physiological function is conventionally thought to be the transport of the weakly water-soluble hormone, cortisol, throughout the circulation <ref>PMID:13395526 </ref>,<ref>PMID:7074030 </ref>. Structural studies of native rat CBG <ref>PMID:17644521 </ref> and a cleaved human CBG-antitrypsin chimera <ref>PMID:18513745 </ref> have corroborated earlier biochemical studies showing that cortisol binds to CBG with a one-to-one stoichiometry. Additionally, CBG is believed to buffer the concentration of free cortisol in the blood, keeping the level constant despite its pulsatile secretion pattern <ref>PMID:9751481 </ref>. CBG is also thought to participate in the stress response by releasing cortisol specifically at inflammatory sites upon cleavage by human neutrophil elastase between residues 344 and 345<ref>PMID:3143075 </ref>. | ||
See also: [[Corticosteroids]] and [[Steroid Hormones and their receptors]]. | |||
==Gene== | ==Gene== | ||
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Previously-solved structures of the human CBG-antitrypsin (Pittsburgh) chimera with cleaved reactive centre loop at 1.84Å and the native rat CBG at 1.9Å confirm that corticosteroid-binding globulin, despite being a non-inhibitory member of the serpin family, undergoes the S-to-R transition just like the inhibitory members <ref>PMID:17644521 </ref>,<ref>PMID:18513745 </ref>. | Previously-solved structures of the human CBG-antitrypsin (Pittsburgh) chimera with cleaved reactive centre loop at 1.84Å and the native rat CBG at 1.9Å confirm that corticosteroid-binding globulin, despite being a non-inhibitory member of the serpin family, undergoes the S-to-R transition just like the inhibitory members <ref>PMID:17644521 </ref>,<ref>PMID:18513745 </ref>. | ||
In its native form, CBG is in the "stressed" conformation and binds cortisol with very high affinity<ref>PMID:17644521 </ref>. | In its native form, CBG is in the "stressed" conformation and binds cortisol with very high affinity<ref>PMID:17644521 </ref>. | ||
Upon cleavage by its target proteinase, believed to be human neutrophil elastase, the protein undergoes structural rearrangements in the main chain at several parts of the serpin fold, resulting in what is conventionally known as the "relaxed" state <ref>PMID:18513745 </ref>,<ref>PMID:3143075 </ref>, as seen <scene name='Corticosteroid-binding_globulin/Cleaved/9'>here</scene>. The main conformational change is the insertion of the entire N-terminal segment of the reactive loop into beta-sheet A where it is incorporated as a <scene name='Corticosteroid-binding_globulin/Cleaved/10'>novel beta-strand</scene>. | |||
''(Click'' <scene name='Corticosteroid-binding_globulin/Native/1'>here</scene> ''to return to structure of CBG in the S-state.) | ''(Click'' <scene name='Corticosteroid-binding_globulin/Native/1'>here</scene> ''to return to structure of CBG in the S-state.) | ||
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==Ligand-binding== | ==Ligand-binding== | ||
The structures show that the ligand binds in a <scene name='Corticosteroid-binding_globulin/ | The structures show that the ligand binds in a <scene name='Corticosteroid-binding_globulin/Native/8'>largely hydrophobic pocket</scene>, where the main interaction between cortisol and CBG is the pi-pi stacking between a key tryptophan residue (371 in humans), and the steroid ring of cortisol. There is also significant polar interaction between some of the polar side chains of the binding pocket residues and oxygen atoms on cortisol. | ||
''Key: Grey residues are hydrophobic, magenta residues are polar, the ligand is coloured orange'' | |||
==Functions== | ==Functions== | ||
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[[Image:Cbg.jpg|400px|left|thumb| Proposed mechanism of cortisol release at sites of inflammation]] | [[Image:Cbg.jpg|400px|left|thumb| Proposed mechanism of cortisol release at sites of inflammation]] | ||
{{Clear}} | |||
==Naturally-occurring genetic variants<ref>PMID: 19643161 </ref>== | |||
''Leuven'' | |||
CBG Leuven has an exon 2 point mutation which changes <scene name='Corticosteroid-binding_globulin/Leu93/1'>Leucine 93</scene> to a histidine, which reduces the binding affinity for cortisol by three-fold, although there appears to be no known clinical implications. | |||
''Lyon'' | |||
CBG Lyon has an exon 5 point mutation which changes <scene name='Corticosteroid-binding_globulin/Asp367/2'>Aspartate 367</scene> to an asparagine. This mutation lies close to the cortisol-binding pocket and reduces cortisol affinity by four-fold. Heterozygotes show reduction in immunoreactive CBG levels and total cortisol levels but were otherwise healthy, while homozygotes presented with fatigue, depressed mood and low blood pressure. | |||
''CBG Null'' | |||
CBG Null is an exon 2 null mutation resulting in premature termination codon corresponding to residue -12 of pro-CBG molecule (G121A). This leads to 50% (heterozygotes) or undetectable (homozygotes) CBG levels, and both hetero- and homozygotes presented with chronic fatigue and low blood pressure | |||
==Conclusion== | ==Conclusion== | ||
Corticosteroid-binding globulin is a very important blood protein that functions not merely as a passive carrier of cortisol, but also as a ready reservoir of the hormone for release at sites of inflammation. It also acts as a buffer to keep the level of blood cortisol constant and thus, maintains homeostasis. Work is still being done, not just in fully elucidating the molecular mechanism of its function, but also in its interaction with various tissues in the body, and this can have great implications on our understanding of metabolic diseases, as well as infection and immunity. | Corticosteroid-binding globulin is a very important blood protein that functions not merely as a passive carrier of cortisol, but also as a ready reservoir of the hormone for release at sites of inflammation. It also acts as a buffer to keep the level of blood cortisol constant and thus, maintains homeostasis. Work is still being done, not just in fully elucidating the molecular mechanism of its function, but also in its interaction with various tissues in the body, and this can have great implications on our understanding of metabolic diseases, as well as infection and immunity. | ||
</StructureSection> | |||
==3D structures of corticosteroid-binding globulin== | |||
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | |||
[[2v95]] – rSer-A6 – rat<br /> | |||
[[2vdx]], [[4c41]] – hSer-A6 (mutant) - human<br /> | |||
[[2vdy]], [[4c49]] – hSer-A6 (mutant) + cortisol<br /> | |||
[[4bb2]] – hSer-A6 (mutant) + progesterone <br /> | |||
==Resources== | ==Resources== | ||
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<references/> | <references/> | ||
[[Category:Topic Page]] | |||
