Corin Mutation R539C from Hypertensive Patients Impairs Zymogen Activation and Generates an Inactive Alternative Ectodomain Fragment

Dong, Ningzheng; Fang, Chaodong; Jiang, Yuan; Zhou, Tiantian; Li, Meng; Zhou, Jianping; Shen, Jianzhong; Fukuda, Koichi; Qin, Jun; Wu, Qingyu

doi:10.1074/jbc.m112.411512

Cited by 59 publications

(51 citation statements)

References 49 publications

(34 reference statements)

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“…After 5 h, the medium was replaced with serum-free Opti-MEM medium. The conditioned medium was collected after 36 h, and matriptase-2 proteins were immunoprecipitated with an anti-V5-antibody and protein A-Sepharose beads, as described previously (31). The cells were lysed in a lysis buffer containing 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1% Nonidet P-40 (v/v), and a protease inhibitor mixture (1:100; Sigma).…”

Section: Methodsmentioning

confidence: 99%

N-Glycosylation Is Required for Matriptase-2 Autoactivation and Ectodomain Shedding

Jiang

Yang

Feng

et al. 2014

Journal of Biological Chemistry

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Background: Matriptase-2 is a hepatic membrane serine protease that regulates hepcidin expression and iron metabolism. Results: Mutations at specific N-glycosylation sites prevented matriptase-2 activation and ectodomain shedding. Conclusion: N-Glycans play an important role in regulating matriptase-2 activity. Significance: The results provide new insights into the mechanism underlying matriptase-2 expression, zymogen activation, and ectodomain shedding.

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Section: Methodsmentioning

confidence: 99%

N-Glycosylation Is Required for Matriptase-2 Autoactivation and Ectodomain Shedding

Jiang

Yang

Feng

et al. 2014

Journal of Biological Chemistry

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“…In functional studies, both T555I/Q568P and R539C proteins were shown on the cell surface. However, corin T555I/Q568P remained in an inactive zymogen form, whereas corin R539C was activated but quickly inactivated by autocleavage (19,51). In this study, corin K317E was found on the cell surface with impaired zymogen activation, whereas corin S472G was found retained in the ER.…”

Section: Discussionmentioning

confidence: 62%

“…Previously, corin mutants T555I/Q568P and R539C, both located in the Fz2 domain, were reported in hypertensive patients (19,20). In functional studies, both T555I/Q568P and R539C proteins were shown on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

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Corin Mutations K317E and S472G from Preeclamptic Patients Alert Zymogen Activation and Cell Surface Targeting

Dong

Zhou²,

Zhang³

et al. 2014

Journal of Biological Chemistry

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Background: Corin is a protease that acts in the pregnant uterus to prevent pregnancy-induced hypertension. Results: Corin mutations K317E and S472G from preeclamptic patients impaired corin zymogen activation and intracellular trafficking, respectively. Conclusion: Mutations in the CORIN gene may impair corin function by different mechanisms. Significance: Genetic variants and mutations disrupting corin function may contribute to pregnancy-induced hypertension in patients.

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“…Another corin gene mutation was identified in a family of hypertensive patients in China. 8 These researchers demonstrated that cells transfected with the mutant allele expressed corin normally in vitro, however, with reduced activity in processing proatrial natriuretic peptide, probably because the mutation altered the structure or function of the enzyme. Small casecontrol studies have begun to demonstrate that serum soluble corin levels may be lower in patients with hypertension and heart failure 9,10 and possibly higher in pregnancy-associated hypertension.…”

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confidence: 99%

Heart of the Matter

Aparicio

Seshadri

2015

Stroke

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Stroke is the leading neurological cause of death and disability, but, despite awareness of many modifiable vascular risk factors for stroke, the United States continues to record 800 000 events each year. Identifying circulating biomarkers associated with a disease outcome, such as stroke or coronary heart disease, has been a time-honored method to improve our understanding of disease pathophysiology and improve risk prediction, but it has proven challenging to identify such markers associated with stroke risk.1 In a recent attempt to identify circulating biomarkers associated with stroke, higher levels of B-type natriuretic peptide (BNP) were found, along with an elevated urinary albumin/creatinine ratio, to be associated with a 30% to 40% greater risk of stroke and transient ischemic attack.2 Natriuretic peptides are biologically plausible biomarkers for stroke risk because of their role in regulation of intravascular volume and blood pressure, and their relationship with cardiac structure and function. The prohormone of BNP, proBNP, is stored within granules in cardiac myocytes and is released when the cardiac myocytes are stretched; this happens with ventricular volume expansion or pressure overload. ProBNP is cleaved by a previously unknown enzyme into 2 fragments: the inactive N-terminal proBNP and the bioactive peptide BNP. The transmembrane serine protease responsible for this cleavage has recently been characterized in vitro and in animal models and named corin because of its abundant presence in the heart. 3,4 In this issue of Stroke, Peng et al 5 describe the results of a case-control study investigating the association of serum levels of corin with first-ever ischemic or hemorrhagic stroke. Consecutive stroke cases (481 ischemic and 116 hemorrhagic) were recruited from 3 Chinese hospitals during 5 months in 2014. Cases were compared with healthy community participants (2498 controls) randomly recruited in 2010 from the district of Suzhou, outside of Shanghai. Overall, women had lower median levels of serum soluble corin than men. In sexstratified analyses, persons with an ischemic or hemorrhagic stroke had lower levels than stroke-free controls. Both women and men were significantly more likely to have either type of stroke if their circulating corin levels were in the lowest quartile. In men, risk of ischemic stroke was 5-fold higher and risk of hemorrhagic stroke was 17.5-fold higher among persons with corin levels in the lowest quartile compared with persons with corin levels in the top quartile. In women, the risks were 3-and 8.5-fold higher, respectively, and risks persisted in multivariable analyses adjusting for conventional stroke risk factors. This is the first study of serum corin levels in stroke patients, and the results should be considered hypothesis generating. Further caution is warranted because the study was restricted to relatively young, Chinese patients with less severe strokes (median NIHSS score was 4).Corin is found in the heart and the kidneys. What are the potential pathoph...

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Corin Mutation R539C from Hypertensive Patients Impairs Zymogen Activation and Generates an Inactive Alternative Ectodomain Fragment

Cited by 59 publications

References 49 publications

N-Glycosylation Is Required for Matriptase-2 Autoactivation and Ectodomain Shedding

N-Glycosylation Is Required for Matriptase-2 Autoactivation and Ectodomain Shedding

Corin Mutations K317E and S472G from Preeclamptic Patients Alert Zymogen Activation and Cell Surface Targeting

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