Modulation of receptor binding to collagen by glycosylated 5‐hydroxylysine: Chemical biology approaches made feasible by Carpino's Fmoc group,Peptide Science

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Modulation of receptor binding to collagen by glycosylated 5‐hydroxylysine: Chemical biology approaches made feasible by Carpino's Fmoc group
Peptide Science ( IF 1.5 ) Pub Date : 2020-03-19 , DOI: 10.1002/pep2.24156
Maré Cudic ₁ , Gregg B Fields ₁

Affiliation

The creation of the 9‐fluorenylmethoxycarbonyl (Fmoc) group by the Carpino laboratory facilitated the synthesis of peptides containing acid‐sensitive groups, such as O‐linked glycosides. To fully investigative collagen biochemistry, one needs to assemble peptides that possess glycosylated 5‐hydroxylysine (Hyl). A convenient method for the synthesis of Fmoc‐Hyl(ε‐tert‐butyloxycarbonyl (Boc), O‐tert‐butyldimethylsilyl [TBDMS]) and efficient methods for the synthesis of Fmoc‐Hyl[ε‐Boc,O‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D‐galactopyranosyl)] have been developed. Glycosylated Fmoc‐Hyl derivatives were used to construct a series of types I‐IV collagen‐model triple‐helical peptides (THPs) that incorporated known or proposed receptor binding sites. Glycosylation of Hyl was found to strongly down‐regulate the binding of CD44 and the α3β1 integrin to collagen, while the impact on α2β1 integrin binding was more modest. Molecular modeling of integrin binding indicated that Hyl glycosylation directly impacted the association between the α3β1 integrin metal ion‐dependent adhesion site (MIDAS) and the receptor binding site within type IV collagen. The Fmoc solid‐phase strategy ultimately allowed for chemical biology approaches to be utilized to study tumor cell interactions with glycosylated collagen sequences and document the modulation of receptor interactions by Hyl post‐translational modification.

中文翻译：

通过糖基化 5-羟基赖氨酸调节受体与胶原蛋白的结合：Carpino 的 Fmoc 小组使化学生物学方法变得可行

Carpino 实验室创建的 9-芴甲氧基羰基 (Fmoc) 基团促进了含有酸敏感基团（例如O连接糖苷）的肽的合成。为了全面研究胶原蛋白的生物化学，需要组装具有糖基化 5-羟基赖氨酸 (Hyl) 的肽。一种简便的合成Fmoc-Hyl(ε-叔丁氧羰基(Boc), O-叔丁基二甲基甲硅烷基[TBDMS])的方法和高效的合成Fmoc-Hyl[ε-Boc, O ‐(2,3 ,4,6-四-O-乙酰基-β-D-吡喃半乳糖基)]已被开发出来。糖基化 Fmoc-Hyl 衍生物用于构建一系列 I-IV 型胶原模型三螺旋肽 (THP)，其中包含已知或提议的受体结合位点。研究发现，Hyl 的糖基化会强烈下调 CD44 和 α3β1 整合素与胶原蛋白的结合，而对 α2β1 整合素结合的影响则较为温和。整合素结合的分子模型表明，Hyl 糖基化直接影响 α3β1 整合素金属离子依赖性粘附位点 (MIDAS) 与 IV 型胶原内受体结合位点之间的关联。 Fmoc 固相策略最终允许利用化学生物学方法来研究肿瘤细胞与糖基化胶原序列的相互作用，并记录 Hyl 翻译后修饰对受体相互作用的调节。

更新日期：2020-03-19

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