Human Alpha-Fetoprotein and Its Purification by Chromatography on Immobilized Estrogens

Tatarinov, Yu. S.; Terentiev, A. A.; Moldogazieva, N T; Tagirova, Albina

doi:10.1159/000217697

Cited by 9 publications

(5 citation statements)

References 7 publications

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“…Although HAFP was initially reported to bind few, if any, estrogenic steroids (124), additional evidence now indicates that HAFP (obtained by butanol extraction of fetal tissues) can bind to immobilized estrogen columns, suggesting the existence of a partially occluded binding site (125). Previous data had implied that <1.0% of the HAFP population was capable of such binding (126,127) and that the butanol either induced a conformational change or removed a bound ligand that normally interferes with the estrogen binding site (127).…”

Section: Interactions Of Afp With Estrogen During Developmentmentioning

confidence: 99%

Biological Roles of Alpha-Fetoprotein During Pregnancy and Perinatal Development

Mizejewski

2004

Exp Biol Med (Maywood)

122

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The use of alpha-fetoprotein (AFP) as a serum marker in cancer actually predates its employment in the detection of congenital defects; however, the latter use of AFP as a fetal defect marker has propelled its clinical utilization. Although the serum-marker capacity of AFP has long been exploited, less is known of the biological activities of this oncofetal protein during fetal and perinatal development. In the present review, the biological activities of AFP are discussed in light of this glycoprotein's presence in various biological fluid compartments: embryonic and fetal tissues, serum, urine, and reproductive fluids. After a review of the histochemical detection of AFP in various cells and tissues during development, AFP concentrations within various biological fluids were discussed in the context of gestational age and anatomic location. Discussion follows concerning the relationships and roles of AFP in developmental events such as erthyropoiesis, histogenesis/organogenesis, and ligand binding and in developmental disorders such as hypothyroidism, folate deficiencies, and acquired immunodeficiency disorder (AIDS). Based on its association with so many types of birth defects, malformations, and congenital anomalies, AFP can be viewed as a molecular "troubleshooter" until signal transduction pathways are established during pregnancy and prenatal development. The review concludes with a discussion of the place of AFP in the rapidly expanding field of proteomics.

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Section: Interactions Of Afp With Estrogen During Developmentmentioning

confidence: 99%

Biological Roles of Alpha-Fetoprotein During Pregnancy and Perinatal Development

Mizejewski

2004

Exp Biol Med (Maywood)

122

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“…4, lower left). This hypothetical form (MG) of HAFP might comprise only 1.0% or less of the total circulating fetal protein (247), but might be expected to increase in the presence of fetal defects (173) and be the estrogen-binding form of HAFP previously described (339,340).…”

Section: Denatured Intermediates and The Mgfmentioning

confidence: 99%

Alpha-fetoprotein Structure and Function: Relevance to Isoforms, Epitopes, and Conformational Variants

Mizejewski

2001

Exp Biol Med (Maywood)

247

205

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Mammalian alpha-fetoproteln (AFP) Is classified as a member of the albuminoid gene superfamily consisting of albumin, AFP, vitamin D (Gc) protein, and alpha-albumin. Molecular variants of AFP have long been reported In the biomedical literature. Early studies Identified Isoelectrlc pH isoforms and lectin-binding variants of AFP, which differed In their physicochemical properties, but not In amino acid composition. Genetic variants of AFP, differing in mRNA kllobase length, were later extensively described in rodent models during fetal/perinatal stages, carcinogenesis, and organ regeneration. With the advent of monoclonal antibodies in the early 1980s, multiple antigenic epitopes on native AFP were detected and categorized, culminating In the Identification of six to seven major epltopes. During this period, various AFP-blndlng proteins and receptors were reported to inhibit certain AFP Immunoreactlons. Concomlttantly, human and rodent AFP were cloned and the amino acid sequences of the translated proteins were divulged. Once the amino acid composition of the AFP molecule was known, enzymatic fragments could be identified and synthetic peptide segments synthesized. Following discovery of the molten globule form In 1981,the existence of transitory, intermediate forms of AFP were acknowledged and their physiological significance was realized. In the present review, the various Isoforms and variants of AFP are discussed In light of their potential biological relevance.

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“…In our previous work, we studied binding of a single ligand, DES, to a HAFP modeled structure. This was dictated by experimental data obtained by our group, which demonstrated the high binding efficiency of immobilized DES to HAFP [30]. Molecular docking of DES to the HAFP 3D model and subsequent MD simulation of the obtained complex allowed identification of amino acid residues involved in HAFP-DES interaction.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of hormone-binding transport proteins to interfere with ER-ligand interactions dictates the importance of investigation of binding affinities of both estrogens and ER disruptors to both ERs and estrogen-binding transport proteins, such as AFP. Rodent AFPs have been experimentally evidenced to bind free estrogens, while HAFP has been shown to bind only immobilized estrogens [29,30]. Using chimeric human-rat AFP, the existence of two types of estrogen-binding sites (high-affinity and low-affinity) in rat AFP has been proposed [31,32].…”

Section: Introductionmentioning

confidence: 99%

Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis

Moldogazieva

Ostroverkhova

Кузьмич

et al. 2020

IJMS

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Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting a variety of hydrophobic ligands, including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth, which can be attributed to its estrogen-binding ability. Despite AFP having long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP–ligand interaction remains obscure. In our study, we constructed a homology-based 3D model of human AFP (HAFP) with the purpose of molecular docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol), and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on the ligand-docked scoring functions, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity binding sites were located (i) in a tunnel formed within HAFP subdomains IB and IIA and (ii) on the opposite side of the molecule in a groove originating from a cavity formed between domains I and III, while (iii) the third low-affinity binding site was found at the bottom of the cavity. Here, 100 ns molecular dynamics (MD) simulation allowed us to study their geometries and showed that HAFP–estrogen interactions were caused by van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP–antiestrogen binding. Molecular mechanics/Generalized Born surface area (MM/GBSA) rescoring method exploited for estimation of binding free energies (ΔGbind) showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP–ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues, along with two disulfide bonds (Cys224–Cys270 and Cys269–Cys277), have key roles in both HAFP–estrogen and HAFP–antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein–ligand interactions and anticancer therapy strategies based on ERα-binding ligands.

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Human Alpha-Fetoprotein and Its Purification by Chromatography on Immobilized Estrogens

Cited by 9 publications

References 7 publications

Biological Roles of Alpha-Fetoprotein During Pregnancy and Perinatal Development

Biological Roles of Alpha-Fetoprotein During Pregnancy and Perinatal Development

Alpha-fetoprotein Structure and Function: Relevance to Isoforms, Epitopes, and Conformational Variants

Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis

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