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FUT10和FUT11是修饰蛋白质EMI结构域的蛋白质O-岩藻糖基转移酶。

FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains.

作者信息

Hao Huilin, Yuan Youxi, Ito Atsuko, Eberand Benjamin M, Tjondro Harry, Cielesh Michelle, Norris Nicholas, Moreno Cesar L, Maxwell Joshua W C, Neely G Gregory, Payne Richard J, Kebede Melkam A, Urbauer Ramona J Bieber, Passam Freda H, Larance Mark, Haltiwanger Robert S

机构信息

Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.

Regional Fish Institute, Ltd., Kyoto, Japan.

出版信息

Nat Chem Biol. 2025 Apr;21(4):598-610. doi: 10.1038/s41589-024-01815-x. Epub 2025 Jan 7.

DOI:10.1038/s41589-024-01815-x
PMID:39775168
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11949838/
Abstract

O-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established O-fucosylation of epidermal growth factor-like repeats by protein O-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of O-fucosylation on the elastin microfibril interface (EMI) domain of Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis and CRISPR-Cas9 knockouts, we demonstrate that FUT10 and FUT11, originally annotated in UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, we renamed them as POFUT3 and POFUT4, respectively. Like POFUT1/2, POFUT3/4 function in the endoplasmic reticulum, require folded domain structures for modification and participate in a non-canonical endoplasmic reticulum quality control pathway for EMI domain-containing protein secretion. This finding expands the O-fucosylation repertoire and provides an entry point for further exploration in this emerging field of O-fucosylation.

摘要

O-岩藻糖基化在各种重要的生物学事件中发挥着关键作用。除了已确定的由蛋白质O-岩藻糖基转移酶1（POFUT1）对表皮生长因子样重复序列进行的O-岩藻糖基化以及由POFUT2对血小板反应蛋白1型重复序列进行的O-岩藻糖基化外，我们最近在多聚蛋白-1（MMRN1）的弹性蛋白微原纤维界面（EMI）结构域上发现了一种O-岩藻糖基化类型。在这里，我们使用AlphaFold2筛选、免疫共沉淀、酶促分析结合质谱分析以及CRISPR-Cas9基因敲除技术，证明最初在UniProt中注释为α1,3-岩藻糖基转移酶的FUT10和FUT11实际上是负责修饰EMI结构域的POFUT；因此，我们分别将它们重新命名为POFUT3和POFUT4。与POFUT1/2一样，POFUT3/4在内质网中发挥作用，需要折叠的结构域结构进行修饰，并参与含EMI结构域蛋白分泌的非经典内质网质量控制途径。这一发现扩展了O-岩藻糖基化的种类，并为在这个新兴的O-岩藻糖基化领域进行进一步探索提供了切入点。

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