The Amino Terminal Regions of proBNP and proANP Oligomerise through Leucine Zipper-like Coiled-coil Motifs

Seidler, Tim; Pemberton, Chris J.; Yandle, Tim G.; Espiner, Eric A.; Nicholls, Gary; Richards, Mark

doi:10.1006/bbrc.1999.0225

Cited by 66 publications

(47 citation statements)

References 28 publications

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“…These results demonstrate that, again like NT-proBNP [8], proBNP, and HEK-proBNP are monomers in solution. For proBNP, this observation contradicts an earlier study [15] stating that proBNP is either a trimer or tetramer. Our data lend further support to the conclusion of [9] that the "high-molecularweight component" discussed previously [15,17] is unlikely to be an oligomer of NT-proBNP or proBNP.…”

Section: Resultscontrasting

confidence: 91%

“…The oligomeric nature of NT-proBNP and proBNP has produced conflicting results. An earlier study stated that each may be a trimer or tetramer based on a predictive assessment of coiledcoil domains in the NT-proBNP fragment and elution positions of each on size-exclusion chromatography run under benign neutral pH conditions [15]. A detailed physicochemical study using CD, size-exclusion chromatography, and sedimentation equilibrium AUC [7] demonstrated that NT-proBNP at moderate concentration in neutral pH physiologically relevant buffer conditions was actually a monomer.…”

mentioning

confidence: 99%

“…The expected value for the mixture was found, thereby ruling out an interfering substance in the HEKproBNP sample. [15] stating that proBNP is either a trimer or tetramer. Our data lend further support to the conclusion of [9] that the "high-molecularweight component" discussed previously [15,17] is unlikely to be an oligomer of NT-proBNP or proBNP.…”

mentioning

confidence: 99%

“…[15] stating that proBNP is either a trimer or tetramer. Our data lend further support to the conclusion of [9] that the "high-molecularweight component" discussed previously [15,17] is unlikely to be an oligomer of NT-proBNP or proBNP. Interestingly, the four identified O-linked carbohydrate sites in HEK-proBNP have no obvious influence on either the secondary or quaternary structure of proBNP and presumably NT-proBNP as well.…”

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confidence: 99%

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A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein

Crimmins

Kao

2008

Archives of Biochemistry and Biophysics

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The N-terminal fragment of pro B-type natriuretic peptide (NT-proBNP) and proBNP are used as gold standard clinical markers of myocardial dysfunction such as cardiac hypertrophy and left ventricle heart failure. The actual circulating molecular forms of these peptides have been the subject of intense investigation particularly since these analytes are measured in clinical assays. Conflicting data has been reported and no firm consensus on the exact nature of the molecular species exists. Because these clinical assays are immunoassay-based, specific epitopes are detected. It is conceivable then that certain epitopes may be masked and therefore unavailable for antibody binding, thus the importance of determining the nature of the circulating molecular forms of these analytes. This situation is an unavoidable Achilles' heel of immunoassays in general.A recombinant O-linked glycosylated form of proBNP has been show to mimic some of the properties of extracted plasma from a heart failure patient. In particular the recombinant and native material co-migrated as diffuse Western-immunostained bands on SDS-PAGE and each band collapsed to an apparent homogeneous band following deglycosylation. Thus, glycosylated-proBNP may be one such circulating form. Here we provide extensive physiochemical characterization for this O-linked protein and compare these results to other described circulating species, non-glycosylated-proBNP and NT-proBNP. It will be shown that glycosylation has no influence on the secondary and quaternary structure of proBNP. In fact, at moderate concentration in benign physiological neutral pH buffer, all three likely circulating species are essentially devoid of major secondary structure, i.e., are intrinsically unstructured proteins (IUPs). Furthermore, all three proteins exist as monomers in solution. These results may have important implications in the design of NT-proBNP/BNP immunoassays. Immunoassays utilize antibodies that react with specific analyte (usually protein) epitope(s). If these epitopes become unreactive due to say proteolytic processing, or masked by interaction with other molecule(s), or are post-or co-translationally modified, then the immunoassay can generate incorrect results. It becomes important then to identify the circulating forms of the analytes. This analysis can include primary sequence, post-translational modifications, and quaternary structure as homo-and hetero-interaction partners. Knowledge of such can aid in the development of immunoassays that accurately detect the circulating species. Keywords GlycosylatedPrevious characterization of human NT-proBNP whether as a recombinant product or synthetic peptide showed this N-terminal fragment to be a largely unfolded, flexible protein, termed an IUP, which exists as a monomer in solution [7,8]. No comparable data were hitherto available for proBNP and a recently discovered [9] glycosylated form of proBNP. Here we use a combination of CD to assess the global average secondary structure of proBNP and glycosylated-proBNP...

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Section: Resultscontrasting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein

Crimmins

Kao

2008

Archives of Biochemistry and Biophysics

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“…Plasma was separated within 20 min by centrifugation and stored at À 80 1C. Plasma was assayed for atrial natriuretic peptide (ANP), 13 N-terminal ANP (NT-proANP), 14 B-type natriuretic peptide (BNP), 15 N-terminal B-type natriuretic peptide (NT-proBNP), 16 C-type natriuretic pepetide (CNP) 17 and cyclic guanosine monophosphate (cGMP). 18 Transthoracic echocardiography was performed using a GE Vivid 3 ultrasound system (GE Medical Systems, Waukesha, WI, USA) at Christchurch Hospital and an ATL HDI 5000 (Philips Healthcare, Andover, MA, USA) at Auckland City Hospital.…”

Section: Coronary Disease Cohortmentioning

confidence: 99%

Genetic variation in the renin–angiotensin–aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease

et al. 2012

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This study examined renin-angiotensin-aldosterone (RAAS) system gene variants for associations with cardiovascular risk factors and outcomes in coronary heart disease. Coronary disease patients (n ¼ 1186) were genotyped for 21 single-nucleotide polymorphisms (SNPs) within angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin-II type-1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Associations with all-cause mortality and cardiovascular readmissions were assessed over a median of 3.0 years. The AGT M235T 'T' allele was associated with a younger age of clinical coronary disease onset (P ¼ 0.006), and the AGT rs2478545 minor allele was associated with lower circulating natriuretic peptides (P ¼ 0.0001-P ¼ 0.001) and E/E 1 (P ¼ 0.018). Minor alleles of AGT SNPs rs1926723 and rs11122576 were associated with more frequent history of renal disease (Pp0.04) and type-2 diabetes (Pp0.02), higher body mass index (Pp0.02) and greater mortality (Pp0.007). AGT rs11568054 minor allele carriers had more frequent history of renal disease (P ¼ 0.04) and higher plasma creatinine (P ¼ 0.033). AGT rs6687360 minor allele carriers exhibited worse survival (P ¼ 0.02). ACE rs4267385 was associated with older clinical coronary disease onset (P ¼ 0.008) and hypertension (P ¼ 0.013) onset, increased plasma creatinine (P ¼ 0.01), yet greater mortality (P ¼ 0.044). Less history of hypertension was observed with the AGTR1 rs12685977 minor allele (P ¼ 0.039). Genetic variation within the RAAS was associated with cardiovascular risk factors and accordingly poorer survival.

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An amyloidogenic determinant in n‐terminal pro‐brain natriuretic peptide (nt‐probnp): Implications for cardiac amyloidoses

et al. 2011

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Deposition of amyloid in the atria (isolated atrial/cardiac amyloid) is fairly common in the aging heart. It consists of amyloid fibrils, formed both by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the precursor molecule of ANP, proANP. This study examines whether amyloidogenic determinants (short peptides/amyloid forming favoring regions) exist in the sequence of NT-proBNP, the N-terminal part of proBNP, and if these determinants form amyloid-like fibrils in vitro. We have predicted a possible amyloidogenic determinant in the sequence of the NT-proBNP, and we conclusively show, after its synthesis, that it forms amyloid-like fibrils in vitro, utilizing transmission electron microscopy, X-ray diffraction, attenuated total reflectance Fourier-transform infrared spectroscopy, and polarizing microscopy. Thus, for the first time, in this study, a possible biological role is attributed to a certain, specific part of this important cardiac prohormone/natriuretic peptide, which acts as an important biomarker indicative of heart failure. Its possible direct involvement in isolated cardiac amyloidosis, atrial fibrillation, and other types of cardiac amyloidoses is indicated and discussed. Since these cardiac hormones and their prohormones play key roles in cardiovascular homeostasis through natriuresis, diuresis, vasorelaxation, and inhibition of renin and aldosterone secretion (pathophysiology of hypertension and cardiovascular regulation), we also try to suggest these specific, short peptides as possible future structural targets of efforts toward inhibiting formation of natriuretic peptide(s) amyloid.

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The Amino Terminal Regions of proBNP and proANP Oligomerise through Leucine Zipper-like Coiled-coil Motifs

Cited by 66 publications

References 28 publications

A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein

A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein

Genetic variation in the renin–angiotensin–aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease

An amyloidogenic determinant in n‐terminal pro‐brain natriuretic peptide (nt‐probnp): Implications for cardiac amyloidoses

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