Hormone binding globulins undergo serpin conformational change in inflammation

Pemberton, Philip A.; Stein, Penelope E.; Pepys, Mark B.; Potter, Julia M.; Carrell, Robin W.

doi:10.1038/336257a0

Cited by 391 publications

(278 citation statements)

References 10 publications

Supporting

Mentioning

262

Contrasting

Unclassified

Order By: Relevance

“…This has been seen in all inhibitory serpins tested as well as in the noninhibitory TBG and CBG [44]. Ovalbumin and angiotensinogen notably lack this transition [38].…”

Section: Experimental Clues To Conformational Properties the Occurrenmentioning

confidence: 94%

Structural aspects of serpin inhibition

et al. 1994

View full text Add to dashboard Cite

The essential roles of proteins of the serpin family in many physiological processes, along with new discoveries of their unique folding properties, have attracted intense interest in recent years. Many serpins display unusual mobile behavior attributed to rearrangements of a-helical or /J-sheet domains, whereby large scale transitions accompany a variety of functions, including inactivation. This unusual behavior was first recognized with the X-ray structure of modified al-proteinase inhibitor. Subsequent experiments, including new X-ray structures, have revealed a surprising variety of conformations which are functionally important but only partially understood. We review here experimental evidence for conformations relevant to the serpin inhibitory mechanism.

show abstract

“…This has been seen in all inhibitory serpins tested as well as in the noninhibitory TBG and CBG [44]. Ovalbumin and angiotensinogen notably lack this transition [38].…”

Section: Experimental Clues To Conformational Properties the Occurrenmentioning

confidence: 94%

Structural aspects of serpin inhibition

et al. 1994

View full text Add to dashboard Cite

show abstract

“…However, the serpin family includes also members that show no protease inhibitory activity. These serpins function in diverse biological processes, such as hormone transport (thyroxinebinding globulin) (24), blood pressure regulation (angiotensinogen) (25), tumor suppression (maspin) (26), and angiogenesis (pigment epithelium-derived factor) (27). In other cases, functional, inhibitory serpins display additional activities, as exemplified by C1 inhibitor (C1 INH), which shows anti-inflammatory effects including endotoxin binding (28), and protein C inhibitor (PCI), which exerts direct antimicrobial effects (29).…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

Kalle

Papareddy

Kasetty

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity.

show abstract

“…The release of ligands from CBG at their sites of action is controlled in a targeted manner, as illustrated by crystal structure studies [1]. The best example for this is at sites of inflammation neutrophil elastase cleaves CBG at a single site in a surface exposed reactive center loop, which causes a significant rearrangement in the tertiary structure of CBG that disrupts steroid-binding, thus providing a highly efficient mechanism for the local release of cortisol [11][12][13]. As there is evidence that CBG is the target of other proteinases [9], CBG accumulated at the maternal-fetal interface [6] can be cleaved by placenta-specific proteinases and thus involved in regulating local progesterone bioavailability and action.…”

Section: Special Topicmentioning

confidence: 99%

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Lei

et al. 2012

Sci. China Life Sci.

View full text Add to dashboard Cite

Corticosteroid-binding globulin (CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone. Others and we have reported non-synonymous single nucleotide polymorphisms (SNPs) that influence CBG production or steroid-binding activity. However, no promoter polymorphisms affecting the transcription of human CBG gene (Cbg) have been reported. In the present study we investigated function implications of six promoter SNPs, including 26 C/G, 54 C/T, 144 G/C, 161 A/G, 205 C/A, and 443/444 AG/, five of which are located within the first 205 base pairs of 5′-flanking region and close to the highly conserved footprinted elements, TATA-box, or CCAAT-box. Luciferase reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly enhanced. The first three polymorphisms, 26 C/G, 54 C/T, and 144 G/C located close to the putative hepatic nuclear factor (HNF) 1 binding elements, altered the transactivation effect of HNF1. We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor (GR) , although none of the SNPs affected its transrepression function. Our results suggest that human Cbg 26 C/G, 54 C/T, 144 G/C, and 161 A/G promoter polymorphisms alter transcriptional activity, and further studies are awaited to explore their association with physiological and pathological conditions. , both of which are well-known hormones for pregnancy maintenance or labor onset. While CBG mainly binds >80% of cortisol in human peripheral blood [3], at the maternal-fetal interface CBG will be occupied by the very high concentrations of progesterone, which is several fold higher than those of cortisol [6]. In the circulation of women during mid-late pregnancy, approximately 10% of CBG steroid-binding sites are occupied by progesterone, versus <1% in non-pregnant women [5]. Plasma CBG levels rise progressively through gestation until term pregnancy [7], and so do blood cortisol and progesterone levels. Maternal plasma CBG, total and free cortisol concentrations are reduced in pre-eclampsia and gestational hypertension patients, and this may be a consequence of decreased Cbg synthesis driven by cytokines or increased degradation driven by inflammation [7]. SPECIAL TOPIC

show abstract

Hormone binding globulins undergo serpin conformational change in inflammation

Cited by 391 publications

References 10 publications

Structural aspects of serpin inhibition

Structural aspects of serpin inhibition

Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Contact Info

Product

Resources

About