GalNAc 在粘蛋白型 O-糖基化中的分子识别,Accounts of Chemical Research

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GalNAc 在粘蛋白型 O-糖基化中的分子识别
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2023-02-23 , DOI: 10.1021/acs.accounts.2c00723
Ignacio Sanz-Martinez _{1,

2} , Sandra Pereira _{1,

2} , Pedro Merino _{1,

2} , Francisco Corzana ₃ , Ramon Hurtado-Guerrero _{1,

4,

5}

Affiliation

N-乙酰半乳糖胺 (GalNAc) 型 O-糖基化是一种重要的翻译后修饰 (PTM)，在生物学中发挥着重要作用。这种 PTM 的故障以癌症中存在截短的O聚糖为例。例如，糖蛋白 MUC1 在许多肿瘤组织中过度表达，并且倾向于携带简单的寡糖，允许呈递不同的肿瘤相关抗原，例如 Tn 或 sTn 抗原（GalNAc-α-1-O-Thr/Ser 和Neu5Acα2-6GalNAcα1-O-Ser/Thr）。在其他情况下，例如与成纤维细胞生长因子 23、O的 O-糖基化相关的肿瘤钙质沉着症-聚糖不存在或含量较低。在确定识别 GalNAc 的生物分子的三维结构方面取得了重大进展，例如抗体、凝集素、粘蛋白酶、GalNAc 转移酶和其他糖基转移酶。对这些实体与含 GalNAc 糖肽之间的复合物的分析，在大多数情况下来自晶体学或 NMR 分析，提供了对控制这些糖肽分子识别的关键结构元素的理解。在这里，我们详细描述和比较了这些蛋白质的结合位点，重点关注 GalNAc 部分如何选择性地与它们相互作用。我们还总结了 GalNAc 识别的异同。一般来说，否GalNAc 的-乙酰基与蛋白质，以及 CH-π 接触，其中糖的疏水性 α-面和 NHAc 的甲基可以参与。后一种相互作用通常为选择性提供基础。值得注意的是，这些糖肽的结合主要取决于对糖部分的识别，但有一些例外，例如主要识别肽主链并使用糖促进形状互补或建立有限数量的抗 MUC1 抗体与蛋白质的相互作用。特别关注 GalNAc 部分，我们可以观察到在相同的蛋白质家族中存在一些相互作用的退化，这可能是由于底物的灵活性。然而，当所有研究的蛋白质一起考虑时，尽管每个蛋白质家族都有共同点，除了负责氢键的常见残基（例如 Tyr、His 或 Asp）的存在之外，无法在不同家族之间辨别出任何模式。考虑到粘蛋白酶、糖基转移酶、抗体和凝集素的不同功能，可以预见缺乏模式。最后，重要的是要指出，在带有 GalNAc-α-1-O-Ser 或 GalNAc-α-1-O-Thr 的糖肽溶液中观察到的构象差异也可以在结合态中发现。例如，C1GalT1 酶利用这种独特的特性广泛糖基化两种受体底物。本综述中总结的发现可能有助于治疗性疫苗的合理结构指导开发、用于早期癌症检测的新型诊断工具、

"点击查看英文标题和摘要"

Molecular Recognition of GalNAc in Mucin-Type O-Glycosylation

N-Acetylgalactosamine (GalNAc)-type O-glycosylation is an essential posttranslational modification (PTM) that plays fundamental roles in biology. Malfunction of this PTM is exemplified by the presence of truncated O-glycans in cancer. For instance, the glycoprotein MUC1 is overexpressed in many tumor tissues and tends to carry simple oligosaccharides that allow for the presentation of different tumor-associated antigens, such as the Tn or sTn antigens (GalNAc-α-1-O-Thr/Ser and Neu5Acα2-6GalNAcα1-O-Ser/Thr, respectively). In other cases, such as tumoral calcinosis associated with O-glycosylation of the fibroblast growth factor 23, O-glycans are absent or less abundant. Significant progress has been made in determining the three-dimensional structures of biomolecules that recognize GalNAc, such as antibodies, lectins, mucinases, GalNAc-transferases, and other glycosyltransferases. Analysis of the complexes between these entities and GalNAc-containing glycopeptides, in most cases derived from crystallographic or NMR analysis, provides an understanding of the key structural elements that control molecular recognition of these glycopeptides. Here, we describe and compare the binding sites of these proteins in detail, focusing on how the GalNAc moieties interact selectively with them. We also summarize the differences and similarities in GalNAc recognition. In general, the recognition of GalNAc-containing glycopeptides is determined by hydrogen bonds between hydroxyl groups and the N-acetyl group of GalNAc with proteins, as well as CH-π contacts in which the hydrophobic α-face of the sugar and the methyl group of NHAc can be involved. The latter interaction usually provides the basis for selectivity. It is worth noting that binding of these glycopeptides depends primarily on recognition of the sugar moiety, with some exceptions such as a few anti-MUC1 antibodies that primarily recognize the peptide backbone and use the sugar to facilitate shape complementarity or to establish a limited number of interactions with the protein. Focusing specifically on the GalNAc moiety, we can observe that there is some degeneracy of interactions within the same protein families, likely due to substrate flexibility. However, when all studied proteins are considered together, despite the commonalities within each protein family, no pattern can be discerned between the different families, apart from the presence of common residues such as Tyr, His, or Asp, which are responsible for hydrogen bonds. The lack of a pattern can be anticipated, given the diverse functions of mucinases, glycosyltransferases, antibodies, and lectins. Finally, it is important to point out that the conformational differences observed in solution in glycopeptides bearing GalNAc-α-1-O-Ser or GalNAc-α-1-O-Thr also can be found in the bound state. This unique characteristic is exploited, for instance, by the enzyme C1GalT1 to broadly glycosylate both acceptor substrates. The findings summarized in this review may contribute to the rational structure-guided development of therapeutic vaccines, novel diagnostic tools for early cancer detection, and new cancer treatments for cancer with tailored anti-Tn or anti-STn antibodies or new drugs to inhibit GalNAc-T isoenzymes.

更新日期：2023-02-23

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