Trends in Glycoscience and Glycotechnology
Online ISSN : 1883-2113
Print ISSN : 0915-7352
30 巻 , 172 号
選択された号の論文の29件中1~29を表示しています
MINIREVIEW(ガレクチン特集論文)(英語)
  • Gabriel García Caballero, Joachim C. Manning, Anna-Kristin Ludwig, Fed ...
    2018 年 30 巻 172 号 p. SE1-SE9
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Systematic databank-based sequence comparisons with the cDNA sequence for a lens-specific rat protein localized between lens fiber cells disclosed its similarity to galectins. In mammals, two sequence changes occur within the seven positions of amino acids commonly engaged in contacts to the β-galactoside core of glycans. Taking the compilation of GRIFIN genes to the level of diverse vertebrates revealed an exceptional variability: mammals shared alteration at two sites, birds and reptiles at only one site and amphibians and fish presented complete reconstitution. The homodimeric (proto-type) GRIFINs of chicken and zebrafish thus are active lectins. Crystallographical information for chicken GRIFIN illustrates the contact profile to lactose without one otherwise conserved site due to the Arg-to-Val substitution. That GRIFIN is enormously stable in vertebrate lenses, can act like a glue (or a bridge) due to its structure and interacts with α-crystallin (shown for murine GRIFIN) suggests a role in well-ordered packing of lens proteins. Referring to a likely analogy in plants, oligomeric leguminous lectins, β-sandwich proteins as galectins, are also assumed to participate in depositing and spatially organizing cell contents, here storage proteins in protein bodies and their contact to the membrane in carbohydrate-dependent and -independent manners, a likely case of structural and functional convergence.

  • Joachim C. Manning, Gabriel García Caballero, Federico M. Ruiz, Antoni ...
    2018 年 30 巻 172 号 p. SE11-SE20
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectin-related protein (GRP) is present in vertebrates. Sequence comparisons between GRPs from diverse species reveal an unusually high degree of similarity indicative of a strong positive selection. In solution, human and chicken GRPs are monomers irrespective of the presence of the 36-amino-acid-long extension of the core structure at the N-terminus. They are devoid of ability to bind lactose due to severe deviations from the respective sequence signature. Crystallography disclosed distortion of the binding-site architecture that precludes accommodation of lactose. The recent characterization of expression of chicken GRP (C-GRP) enables complete galectin network analysis in this organism. When tested in a panel of developing and adult organs, C-GRP presence was detected in bursa of Fabricius. Its epithelium and vessels as well as bursal B cells are positive in immunohistochemistry. In the B lymphocytes, C-GRP was predominantly cytoplasmic, whereas the chicken tandem-repeat-type galectin, the second member of the galectin family expressed in these cells, was detected at the surface. Binding of labeled C-GRP to cells and sections was blocked by heparin. These data illustrate disparities in expression and ligand profiles within the galectin family and hereby stimulate interest to perform respective mapping for mammalian GRPs as step to define its physiological function(s).

  • Vincent Denavit, Danny Lainé, Thomas Tremblay, Jacob St-Gelais, Denis ...
    2018 年 30 巻 172 号 p. SE21-SE40
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    The recent discovery of the critical involvement of galectins in cancer progression, and in inflammatory and immune responses, has raised this family of β-D-galactoside-binding proteins to the rank of high-priority drug targets by the scientific community. This report will highlight the relevance of glycochemistry toward the efficient development of synthetic galectins inhibitors with high affinity and selectivity, as small molecules or multivalent glycoconjugates.

  • Shigehiro Kamitori
    2018 年 30 巻 172 号 p. SE41-SE50
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    The galectins are a family of β-galactoside-specific animal lectins that contain a conserved carbohydrate recognition domain (CRD) with approximately 140 amino acid residues. There are 14 members in the mammalian galectin family (galectin-1–10, and 11–15), and they have different specificities for oligosaccharides. X-ray structures of the galectin CRD in complexes with oligosaccharides have provided important clues about the oligosaccharide-recognition mechanisms of galectins giving the different specificities. Galectin is divalent in glycan binding due to the association of two CRDs that crosslink with oligosaccharides. The spatial arrangement of the two CRDs is very important for elucidating the biological functions of galectins. Several different spatial arrangements of CRDs are found in X-ray structures of galectins. I herein examined the three-dimensional structures of galectins relevant for biological functions, based on the protein–ligand interactions related with oligosaccharide-specificity, the cross-linking structure by galectin and oligosaccharides, and the spatial arrangements of CRDs.

  • Tadasu Urashima, Jun Hirabayashi, Sachiko Sato, Akira Kobata
    2018 年 30 巻 172 号 p. SE51-SE65
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    It is now recognized that human milk oligosaccharides (HMOs) can function both as prebiotics and as decoy receptors that inhibit the attachment of pathogenic microorganisms to the colonic mucosa. They can also act as immune modulators and as colonic maturation stimulators in breast-fed infants. These functions could be mediated by biological interaction between a variety of HMOs and lectins including galectins, selectins and siglecs. There are more than 100 HMOs; they have structural units such as H type 1: Fucα1-2Galβ1-3GlcNAc, Lewis a: Galβ1-3(Fucα1-4)GlcNAc, Lewis b: Fucα1-2Galβ1-3(Fucα1-4)GlcNAc, Lewis x: Galβ1-4(Fucα1-3)GlcNAc, sialyl Lewis a: Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc, and sialyl Lewis x: Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc. It can be expected that these units may be utilized as tools for studies on the sugar-binding specificities of lectins including galectins, monoclonal antibodies, virus capsid proteins and bacterial toxins. This mini-review presents the dataset of comprehensive HMO structures, including recently clarified ones, in tabular form, for its utilization in such studies, including those of carbohydrate-binding specificity of galectins. In addition, this review introduces recent in vivo and clinical studies, which may be relevant to the biological functions and future utilization of HMOs.

  • Tomoharu Takeuchi
    2018 年 30 巻 172 号 p. SE67-SE74
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectins are a family of β-galactoside-binding lectins widely distributed among animals and fungi, and Galβ1-4GlcNAc is considered the major recognition unit of vertebrate galectins. On the other hand, more than 10 galectins have been reported in Caenorhabditis elegans that belong to the invertebrate class and these C. elegans galectins have been confirmed to have affinity for Galβ1-4GlcNAc. However, the glycan structure differs among species and glycan containing Galβ1-4GlcNAc has not been reported in C. elegans so far. Therefore, the endogenous ligands of C. elegans galectins remained undetermined. Recent studies uncovered that the structures of endogenous ligand glycans of C. elegans galectins are different from those of vertebrate galectins, for e.g., N-glycan containing Galactoseβ1-4 fucose epitope which is not found in vertebrates. Further, C. elegans galectins play a role in host defense against infection and oxidative stress. The roles of mammalian galectins in host defense have been explored in recent years. Taken together, one of the fundamental functions of galectins is possibly host defense because both C. elegans and mammalian galectins function in host defense despite alterations of their ligand structure in the evolutionary process.

  • Jun Hirabayashi, Dan Hu, Hiroaki Tateno, Naoyuki Kuwabara, Ryuichi Kat ...
    2018 年 30 巻 172 号 p. SE75-SE88
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    The fruiting body of the edible mushroom Agrocybe cylindracea contains a proto-type galectin named ACG, which shows affinity to a wide range of β-galactosides. Unlike other galectins, it also binds to disaccharides (GalNAcα1-3Gal/GalNAc) found in blood group A and Forssman epitopes. Structurally, ACG lacks an evolutionarily conserved Asn located on the S4 strand (Ala64) but is compensated for by Asn46, which is located on the extended loop region unique to this galectin. A recent site-directed mutagenesis study revealed that the N46A mutant had selective affinity to oligosaccharides containing GalNAcα1-3Gal/GalNAc epitopes (Hu et al., (2013) Biochem. J., 453, 261–270). Taking into consideration the previous observation that Pro45 takes the cis conformation, Hu et al. assumed that ACG has evolved to attain two conformations at the imide group of Pro45: a cis conformation, where it can recognize β-galactosides, and a Pro45-tras conformation while it binds to the unique GalNAcα1-3Gal/GalNAc. The proposed dual recognition mechanism was proved through further site-directed mutagenesis and X-ray crystallography analysis. Notably, N46A recognizes even non-reducing terminal disaccharides, GalNAcα1-3Gal/GalNAc. Thus, the one face of this “Janus-type” lectin fulfills the conventional definition of galectins, whereas the other face does not. A possible scenario of galectin deviation is discussed.

  • Junko Nio-Kobayashi
    2018 年 30 巻 172 号 p. SE89-SE96
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectins, β-galactoside-binding lectins, consist of 15 members and are broadly distributed in the mammalian body in organ- and cell-specific manners. This minireview summarizes current knowledge on the cellular localization of galectin subtypes in various organs including the digestive tract, lymphatic system, respiratory system, urinary system, and reproductive system. We also summarize the specific localization of galectins in the epithelium with a focus on the characteristic morphologies of epithelia. In addition, we discuss the functions of galectins in the reproductive and endocrine systems, pathogenic angiogenesis, and the regulation of stem cells. The regulatory mechanism of galectin expression is also discussed based on findings obtained from luteal cells. Various glycoconjugate ligands for galectins have been identified, and notably the ligands for galectins differ in each galectin-expressing cell. The physiological and pathological states of cells affect the expression of galectin and glycoconjugate ligands, and the extracellular environment, such as the concentration of growth factors, nutrients, and oxygen also controls the expression levels. Future studies to identify the cellular and intracellular localization of galectins using histological analyses will provide a better understanding of the potential functions of galectins in healthy and disease states.

  • Verónica C. Martínez Allo, Marta A. Toscano, Nicolás Pinto, Gabriel A. ...
    2018 年 30 巻 172 号 p. SE97-SE107
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    The proper function of the immune system entails multiple regulatory pathways aimed at modulating immunogenic and tolerogenic functions of immune cells. Galectins, a family of carbohydrate-binding proteins, control a variety of biological processes involved in activation, differentiation, trafficking and survival of immune cells. In this review we summarize pioneer work and emerging findings highlighting selected functions of galectins as regulatory checkpoints that control innate and adaptive immune cell programs.

  • Mitsuomi Hirashima, Toshiro Niki, Tsutomu Masaki
    2018 年 30 巻 172 号 p. SE109-SE118
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectin-9 (Gal-9)/Ecalectin was first identified as a T cell-derived eosinophil chemoattractant. We found that Gal-9 plays a role in not only the accumulation but also the activation of eosinophils in experimental allergic models and human allergic patients; Gal-9 was shown to induce eosinophil chemotaxis in vitro and in vivo and activated eosinophils in various aspects. Recent studies, however, showed that Gal-9 has other functions in the differentiation, maturation, aggregation, adhesion, and death of various cells. Presently, we and other groups are in the process of investigating the function of Gal-9 in a variety of physiological and pathological conditions. In this article, we will show the in vivo therapeutic effects of Gal-9 in various disease models (both hyper-immune and immune-compromised conditions), suggesting that Gal-9’s immune function changes according to the context. Indeed, the accumulated evidence suggests that Gal-9 orchestrates a variety of biological phenomena to maintain homeostasis.

  • Yaron Vinik, Hadas Shatz-Azoulay, Yehiel Zick
    2018 年 30 巻 172 号 p. SE119-SE128
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectin-8 (Gal-8) is a member of the galectin family of animal lectins that regulate a myriad of biological processes including cell growth, cell transformation, embryogenesis, apoptosis, cell adhesion and immune responses. Gal-8 expression increases in several, though not all, cancerous tissues including lung, bladder, kidney, prostate, and breast tissues. Based on its prevalence, an estimated ~500,000 newly diagnosed cancer patients/year are expected to possess an amplified Gal-8 gene. Yet, the molecular mechanisms underlying its role in cancer growth and metastasis remain incompletely understood. Here we describe potential modes of action of Gal-8 that might account for its central role in cancer biology. The evidence, gathered thus far, implicates Gal-8 as a driver of a ‘vicious cycle,’ whereby cancer cells that overexpress and secrete Gal-8, benefit from its potential to promote their own growth; potentiate epithelial mesenchymal transition, and induce secretion of metastasis-promoting agents at the metastatic niche that induce further recruitment and seeding of cancer cells. Further in-depth studies related to its mode of action, are expected to support ongoing efforts aimed at implementing Gal-8-targeted therapies for the treatment of cancer patients.

  • Hakon Leffler
    2018 年 30 巻 172 号 p. SE129-SE135
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    The proteins now called galectins were discovered about 1975 based on their galactoside-binding activity, in a quest to find proteins that decode complex cell-surface glycans, to take part in cell adhesion. They were defined and named in 1994 based on conserved β-galactoside binding sites found within their characteristic ~130 amino acid (aa) carbohydrate recognition domains (CRDs). However, already at their initial discovery, it was also realized that galectins reside in the cytosol or nucleus for much of their life time, and reach their galactoside ligands only after non-classical secretion that bypasses the Golgi apparatus. Here some of the early studies (mainly before 1994) will be summarized, and exemplified with some galectin stories. The phylogenetic relationships of vertebrate galectins will be summarized as a background. The galectin field has developed rapidly after 1994 in many directions. A few basic outstanding questions will be raised and briefly discussed. What determines galectin binding affinity and specificity for natural glycoconjugate ligands? What is the functional role of galectin fine specificity for carbohydrates? Is there a functional connection between on one hand the cytosolic and nuclear galectin functions and on the other extracellular/intravesicular activities? Are there regulatory loops?

  • Jun Iwaki, Jun Hirabayashi
    2018 年 30 巻 172 号 p. SE137-SE153
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    To understand the biological functions of lectins, it is important to investigate their sugar-binding specificity. Although galectins are characterized as β-galactoside-binding proteins comprising evolutionarily conserved amino-acid sequences, they have significantly divergent specificities depending on their individual carbohydrate-recognition domains (CRDs). Of the various methods available to analyze lectin-glycan interactions, frontal affinity chromatography is unique in that it provides a quantitative set of dissociation constants (Kd’s) between immobilized lectins and a panel of (>100) fluorescently labeled oligosaccharides. In this article, we provide an overview of the features of galectin specificities with a focus on human galectins based on published data. From the data obtained, comprehensive features of individual CRDs can be systematically understood in terms of branching, and 3′-modifications including sialylation, sulfation, αGal/GalNAc substitutions, β1-3Gal extension, and N-acetyllactosamine repeats. Additionally, we analyze evolutionarily more distant galectin molecules of non-human origins. These findings provide not only basic knowledge but also useful information for their applications: e.g., for engineering superior galectins improved in their specificity and affinity and developing galectin-targeted drugs.

  • Yves St-Pierre, Nicolas Doucet, David Chatenet
    2018 年 30 巻 172 号 p. SE155-SE165
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    Given the critical role of galectins in cancer and other diseases, considerable efforts have been deployed towards the development of carbohydrate-based inhibitors that limit the binding of galectins to glycosylated residues on cell surface receptors. However, despite decades of research, progress in this field has not met expectations. In this article, we discuss the rationale justifying the development of a new class of galectin-specific peptide inhibitors that disrupt the formation of a prototypic galectin and its protumorigenic functions. These dimer interfering peptides (DIPs) represent an interesting alternative—and possibly a complementary avenue—to neutralize galectin-mediated protumoral functions. If validated, the approach could broaden the classes of galectin inhibitors that can be readily generated against other prototypic galectins, and possibly all other galectin subtypes.

  • Michael Demetriou, Ivan R. Nabi, James W. Dennis
    2018 年 30 巻 172 号 p. SE167-SE177
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    Galectins interact with N-acetyllactosamine (LacNAc) epitopes in transmembrane glycoproteins at the cell surface in a multivalent manner forming a “lattice.” The term “galectin lattice” was first used to describe the impact of galectin-3 on immune synapse formation, T cell activation and autoimmunity (Demetriou et al. (2001) Nature 409, 733). The galectin lattice displays rapid exchange of binding partners or stochastic-binding, thereby acting as an intermediary between free diffusion of glycoproteins and stable complexes in the membrane. This includes (i) slowing diffusion and loss of receptor and transporters to coated-pit endocytosis and/or caveolin domains, (ii) slowing the integration of transmembrane phosphatases with signaling microdomains and (iii) promoting turnover (i.e., opposing stability) of cell-cell and focal adhesion complexes. The lattice model classifies galectins as adaptors of glycoprotein functions; regulating their localization, trafficking and thereby activity thresholds. The lattice model has been validated in immune regulation, cell adhesion and motility, and glucose homeostasis in mice. Here we review physical attributes of galectins and their N-glycan ligands and apply logical inference, coupled with convergence of biochemical, cell biology and genetic evidence that provide a strong Bayesian probability for greater utility of the lattice model.

  • Ming-Hsiang Hong, I-Chun Weng, Fu-Tong Liu
    2018 年 30 巻 172 号 p. SE179-SE184
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    Galectins are β-galactoside-recognizing animal lectins distributed both extracellularly and intracellularly. Extracellular galectins can recognize cell surface carbohydrates and initiate cellular responses. Intracellular galectins can control cellular functions independently of carbohydrate recognition. Recently, studies have suggested that intracellular galectins accumulate around damaged endocytic vesicles through the recognition of host glycans exposed to the cytosol, and accumulated galectins further mediate cellular responses. Here, we summarize the current understanding of the molecular mechanisms underlying how intracellular galectins regulate cellular responses through the recognition of glycans in damaged endocytic vesicles.

  • Brian S. Robinson, Connie M. Arthur, Nourine A. Kamili, Sean R. Stowel ...
    2018 年 30 巻 172 号 p. SE185-SE198
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    Galectins regulate a wide variety of biological processes. However, one of the earliest and most common galectin activities is likely their ability to recognize microbes. Galectin binding to microbes can result in direct microbial killing and activation of host immunity, eventually enhancing the ability of a host to eliminate microbes. However, microbes appear to have also evolved the ability to utilize galectins to enhance host attachment, ultimately leading to increased risk for infection. The ability of galectins to directly engage microbes, coupled with their role in regulating host immune function, positions these carbohydrate binding proteins as key factors that can dictate the consequence of microbial exposure. In this way, galectins represent a highly pleiotropic protein family involved in the regulation of a broad range of host-microbial interactions.

  • Sachiko Sato
    2018 年 30 巻 172 号 p. SE199-SE209
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    The glycocalyx is a layer of glycoconjugates found on the surface of both host cells and microorganisms. Information presented on some of the glycans on glycoconjugates is recognized by mammalian glycan-binding proteins, lectins, and these interactions modulate various physiological processes, including host innate immune responses. Lectins and host glycoconjugates are synthesized in the same secretory pathway. One notable exception is a family of soluble β-galactoside-binding lectins, galectins, which are synthesized and accumulated in the cytosol and thereby segregated from their glycan ligands. In cases where pathogenic infection persists and tissue injury occurs, galectins are passively released from injured cells. In addition, galectins are actively secreted through unconventional secretory pathways by inflammation-activated or differentiating cells. Thus, extracellular emergence of galectins is associated with the presence of pathogenic hazards. Evidence from a series of studies suggests that galectins exert multiple immunological effects. Extracellular galectin-3 acts as a damage-associated molecular pattern (DAMP) and adhesion molecule for neutrophils in lungs to initiate a proinflammatory response and to mediate rapid neutrophil migration in lungs infected with pathogenic microorganisms. In this review, the roles of galectin-3 in initial innate immune responses and resolution are discussed together with a historical overview of research on galectins in the secretory pathway and innate immunology.

  • Armand Girard, John L. Magnani
    2018 年 30 巻 172 号 p. SE211-SE220
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    Galectins comprise a relatively large family of carbohydrate-binding proteins that recognize and bind to β-D-galactoside residues expressed on a variety of different molecules. Advances in the study of their biological activities demonstrate potential functions in cancer progression, inflammatory, immune, and fibrotic responses which have recently translated to target the galectins as novel therapeutic strategies to address unmet medical needs. This review will summarize the therapeutic applications of galectin antagonists to treat human diseases currently in clinical trials.

GLYCOESSAY(ガレクチン特集論文)(英語)
追悼(英語)
MINIREVIEW(ガレクチン特集論文)(日本語)
  • 神鳥 成弘
    2018 年 30 巻 172 号 p. SJ1-SJ10
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    ガレクチンは、β結合をしたガラクトースを特異的に認識するレクチンで、およそ140アミノ酸からなる糖鎖認識ドメイン(CRD)を持つ。哺乳類のガレクチンは、ガレクチン1~15が知られており、ガレクチンの個々のCRDは異なる糖鎖親和性を持つ。ガレクチンCRDと各種糖鎖とのX線結晶構造解析からCRDの糖鎖認識機構が明らかとなってきた。ガレクチンは、通常2つのCRDが会合して2価の糖鎖結合部位を持ち、糖鎖と糖鎖を架橋することにより機能していると考えられている。2つのCRDの空間配置とガレクチンが持つ機能との関係は大変興味深い。ガレクチンのX線結晶構造解析では、CRDの空間配置についていくつかの様式が報告されている。ここでは、ガレクチンの3D構造について、タンパク質・リガンド相互作用と糖鎖親和性との関係、およびガレクチンCRDの空間配置に焦点を絞って述べる。

  • 浦島 匡, 平林 淳, 佐藤 祥子, 木幡 陽
    2018 年 30 巻 172 号 p. SJ11-SJ24
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    ヒトミルクオリゴ糖(HMO)は、母乳栄養児においてプレバイオティクス,感染防御,免疫調整,腸管成熟などの生物機能を担っている。感染防御や抗炎症などの機能性にはガレクチン,セレクチン,シグレックなどのレクチンと多種類のHMOとの相互作用が関わっていると予想される。一方100種類以上含まれるHMOはHタイプ1,ルイスa,ルイスb,ルイスx,シアリルルイスa,シアリルルイスxなどの構造単位を有しているので、各種内在性レクチンやモノクローナル抗体、ウィルスカプシドタンパク質、細菌毒素などの糖結合特異性研究用やレクチン阻害剤の開発のためのツールとしての活用が期待できる。このミニレビューは、最近の構造解析結果も含む網羅的なHMOの構造データセットをガレクチンの糖結合特異性などの研究のための情報ソースとして提示している。またミルクオリゴ糖の機能や利用についての最近のin vivoならびにヒト臨床研究例の紹介も行った。

  • 武内 智春
    2018 年 30 巻 172 号 p. SJ25-SJ32
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    ガレクチンは幅広い生物に分布するβガラクトシド結合性のレクチンであり、脊椎動物ガレクチンのおもなリガンド糖鎖ユニットはGalβ1-4GlcNAcと考えられている。一方、無脊椎動物に含まれる線虫Caenorhabditis elegansにおいて10以上のガレクチンが存在し、それらもGalβ1-4GlcNAcを認識する。しかし、糖鎖の構造は生物種によって異なっており、線虫にはGalβ1-4GlcNAcが存在しないため、線虫ガレクチンの内在性リガンドは不明であった。近年、線虫C. elegansガレクチンは、脊椎動物のガレクチンとは大きく異なる糖鎖、例えば、脊椎動物に発見されていない、N型糖鎖に存在するGalβ1-4Fucエピトープ、をその内在性リガンドとすること、またおもに感染や酸化ストレスに対する生体防御に働くことがわかってきた。近年、哺乳動物などのガレクチンの生体防御における役割が注目されている。線虫と哺乳動物でリガンド糖鎖構造が違うにも関わらず、いずれのガレクチンも生体防御において働いていることから、ガレクチンの基本的な役割の一つは生体防御であることが示唆される。

  • 平林 淳, 胡 丹, 舘野 浩章, 桑原 直之, 加藤 龍一, 八木 史郎
    2018 年 30 巻 172 号 p. SJ33-SJ46
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    食用キノコの一種であるAgrocybe cylindracea(和名:ヤナギマツタケ)の子実体にはACGと名づけられたプロト型のガレクチンが含まれる。ACGは他のガレクチンと異なり、血液型A抗原やフォルスマン抗原に含まれるGalNAcα1-3Gal/GalNAcという二糖構造にも結合する。ACGの構造はS4ストランドに配置される進化的に保存された65位のAsnを欠くが(Ala65)、この欠損は本分子に特徴的な伸張したループ領域に存在するAsn46によって補われている。最近行われた部位特異的変異導入によって、このAsn46をAlaに置換したN46A変異体が上記GalNAcα1-3Gal/GalNAc二糖構造を含むオリゴ糖に選択的に結合することが示された。胡らは、Pro45がシス型で存在するという以前の観察結果から、ACGがPro45のイミド基を介し二つのコンフォメーションをとると推定した。すなわち、シス型ではβガラクトシド構造を認識し、一方トランス型では上記GalNAcα1-3Gal/GalNAc構造を認識するというものだ。この二重認識という推定メカニズムが実際に正しいことが、その後の部位特異的変異実験とX線結晶解析によって証明された。ここで注目すべきは、N46A変異体が認識しているのは非還元末端GalNAcα1-3Gal/GalNAcという二糖部分のみだということだ。「ヤヌス型」と呼べる二つの顔を持った本レクチンは、一側面では従来のガレクチンの定義を満たすが、他側面ではもはや満たさない。ガレクチンが進化の過程で逸脱する過程を構想してみた。

  • 小林(仁尾) 純子
    2018 年 30 巻 172 号 p. SJ47-SJ53
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    ガレクチンはβ-galactoside結合レクチンで、15種類のサブタイプが臓器および細胞特異的に生体内に広く分布する。このミニレビューでは、消化器系、リンパ系、呼吸器系、泌尿器系、そして生殖器系器官などのさまざまな臓器におけるガレクチンサブタイプの組織学的な局在をまとめた。また、上皮の形態学的特徴に注目して、上皮におけるガレクチンの局在についてまとめた。さらに、生殖器および内分泌系組織、病的な血管新生、幹細胞の機能制御におけるガレクチンの役割について考察した。黄体細胞で得られた所見に基づいて、ガレクチンの発現調節機構についても考察している。これまでに様々な複合糖質がガレクチンのリガンドとして同定されているが、ガレクチンを発現する細胞により、リガンドとなる複合糖質は異なる。細胞の生理学的および病理学的な状態が、ガレクチン発現、および、細胞が発現する糖鎖構造に影響を与える。成長因子、栄養素、酸素濃度などの細胞外環境がこれらを調節しているのだろう。組織学的な解析手法を用いて、ガレクチンを発現する細胞を同定し、細胞内局在を明らかにしていくことは、ガレクチンの本質的な機能を理解するための重要な情報を提供するだろう。

  • 平島 光臣, 仁木 敏朗, 正木 勉
    2018 年 30 巻 172 号 p. SJ55-SJ64
    発行日: 2018/01/25
    公開日: 2018/01/25
    ジャーナル オープンアクセス

    Galectin-9(Gal9)/Ecalectinは細胞由来の好酸球遊走因子として同定された。Gal-9はアレルギーモデル動物やアレルギー患者の好酸球集積や活性化に置いて役割を示している。なぜならGal-9はin vitroおよびin vivoで遊走活性を示すとともに色々な局面で活性化の機能も示すと考えられる。最近の研究では好酸球に限らず種々の細胞に対して分化・成熟、凝集、接着、細胞死などでの機能を果たしていることが示されている。現在、我々を含む多くの研究者によって生理的および病的な状態におけるGal-9機能について研究が進められている。本稿では種々の疾病モデル(過剰免疫や免疫低下状態など)でGal-9が治療的効果を示す結果を紹介するが、このことはGal-9が恒常性を保つことで優しい生理活性物質としての役割を演じていると予想される。

  • 岩城 隼, 平林 淳
    2018 年 30 巻 172 号 p. SJ65-SJ81
    発行日: 2018/05/25
    公開日: 2018/05/25
    ジャーナル オープンアクセス

    レクチンの生物機能を知る上で、最初にその基本特性と言うべき糖結合特異性を調べることが肝要である。ガレクチンは進化的に保存されたアミノ酸配列で構成されるβガラクトシド結合タンパク質として特徴付けられるが、個々の糖認識ドメイン(CRD)は多様化しており、その特異性も多様な性質を示す。レクチン–糖鎖間の相互作用を分析する手法は様々あるが、フロンタル・アフィニティクロマトグラフィー(FAC)は固定化レクチンと100種以上もの蛍光標識オリゴ糖間に対する解離定数(Kd)を一斉に提供しうる唯一の方法である。本章では公表されたKd値に基づいて、ヒトガレクチンを中心に各分子の特異性を議論する。網羅的なデータを分析すると、個々のCRDの特異性は分岐構造とβガラクトシド3位水酸基の修飾(シアリル化、硫酸化、αGal/GalNAc付加、β1-3Gal伸長、N-アセチルラクトサミンの繰り返し)という観点から整理することができそうである。加えて、進化的に離れているヒト以外のガレクチンについても、上記特異性に関する統一則は当てはまることが示された。これらの知見は、特異性や親和性を改良した人工ガレクチンを生み出すタンパク質工学や、ガレクチンを標的とした薬剤開発などの応用面でも有益な情報を与えるだろう。

GLYCOESSAY(ガレクチン特集論文)(日本語)
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