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The transfer of transthyretin and receptor-binding properties from the plasma retinol-binding protein to the epididymal retinoic acid-binding protein.

ABSTRACT: Members of the lipocalin superfamily share a common structural fold, but differ from each other with respect to the molecules with which they interact. They all contain eight beta-strands (A-H) that fold to form a well-defined beta-barrel, which harbours a binding pocket for hydrophobic ligands. These strands are connected by loops that vary in size and structure and make up the closed and open ends of the pocket. In addition to binding ligands, some members of the family interact with other macromolecules, the specificity of which is thought to be associated with the variable loop regions. Here, we have investigated whether the macromolecular-recognition properties can be transferred from one member of the family to another. For this, we chose the prototypical lipocalin, the plasma retinol-binding protein (RBP) and its close structural homologue the epididymal retinoic acid-binding protein (ERABP). RBP exhibits three molecular-recognition properties: it binds to retinol, to transthyretin (TTR) and to a cell-surface receptor. ERABP binds retinoic acid, but whether it interacts with other macromolecules is not known. Here, we show that ERABP does not bind to TTR and the RBP receptor, but when the loops of RBP near the open end of the pocket (L-1, L-2 and L-3, connecting beta-strands A-B, C-D and E-F, respectively) were substituted into the corresponding regions of ERABP, the resulting chimaera acquired the ability to bind TTR and the receptor. L-2 and L-3 were found to be the major determinants of the receptor- and TTR-binding specificities respectively. Thus we demonstrate that lipocalins serve as excellent scaffolds for engineering novel biological functions.

SUBMITTER: Sundaram M

PROVIDER: S-EPMC1222385 | biostudies-other | 2002 Mar

REPOSITORIES: biostudies-other

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Project description:Importance:Transthyretin cardiac amyloidosis (ATTR) is an underrecognized cause of heart failure (HF) in older individuals, owing in part to difficulty in diagnosis. ATTR can result from substitution of valine for isoleucine at codon 122 of the transthyretin (TTR) gene (V122I), present in 3.43% of African American individuals. Objective:To examine whether serum retinol-binding protein 4 (RBP4), an endogenous TTR ligand, could be used as a diagnostic test for ATTR V122I amyloidosis. Design, Setting, and Participants:In this combined prospective and retrospective cohort study performed at a tertiary care referral center, 50 African American patients 60 years or older with nonamyloid HF and cardiac wall thickening prospectively genotyped from September 1, 2014, through December 31, 2015, and a comparator cohort of 25 patients with biopsy-proven ATTR V122I amyloidosis recruited from September 1, 2009, through November 31, 2014, comprised the development cohort. Twenty-seven African American patients and 9 patients with ATTR V122I amyloidosis comprised the validation cohort. Main Outcomes and Measures:Circulating RBP4, TTR, B-type natriuretic peptide (BNP), and troponin I (TnI) concentrations and electrocardiographic, echocardiographic, and clinical characteristics were assessed in all patients. Receiver operating characteristic (ROC) analysis was performed to identify optimal thresholds for ATTR V122I amyloidosis identification. A clinical prediction rule was developed using penalized logistic regression, evaluated using ROC analysis and validated in an independent cohort of cases and controls. Results:Age, sex, and BNP and TnI concentrations were similar between the 25 patients with ATTR V122I amyloidosis (mean [SD] age, 72.2 [7.4] years; 18 male [72%]) and the 50 controls (mean [SD] age, 69.2 [5.7] years; 31 male [62%]). Serum RBP4 concentration was lower in patients with ATTR V122I amyloidosis compared with nonamyloid controls (31.5 vs 49.4 µg/mL, P?<?.001), and the difference persisted after controlling for potential confounding variables. Left ventricular ejection fraction was lower in patients with ATTR V122I amyloidosis (mean [SD], 40% [14%] vs 57% [14%], P?<?.001), whereas interventricular septal diameter was higher (mean [SD], 16 [3] vs 14 [2] mm, P?<?.001). The ROC analysis identified RBP4 as a sensitive identifier of ATTR V122I amyloidosis (area under the curve [AUC]?=?0.78; 95% CI, 0.67-0.88). A clinical prediction algorithm composed of RBP4, TTR, left ventricular ejection fraction, interventricular septal diameter, mean limb lead QRS voltage, and grade 3 diastolic dysfunction yielded excellent discriminatory capacity for ATTR V122I amyloidosis (AUC?=?0.97; 95% CI, 0.93-1.00), whereas a 4-parameter model, including RBP4 concentration, retained excellent discrimination (AUC?=?0.92; 95% CI, 0.86-0.99). The models maintained excellent discrimination in the validation cohort. Conclusions and Relevance:A prediction model using circulating RBP4 concentration and readily available clinical parameters accurately discriminated ATTR V122I amyloidosis from nonamyloid HF in a case-matched cohort. This clinical algorithm may be useful for identification of ATTR V122I amyloidosis in elderly African American patients with HF.

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The transfer of transthyretin and receptor-binding properties from the plasma retinol-binding protein to the epididymal retinoic acid-binding protein.

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