N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy.
N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy.
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DOI：
10.7554/elife.82811
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发表时间：
2023-02-01
期刊：
影响因子：
7.7
通讯作者：
Campbell, Kevin P.
中科院分区：
文献类型：
--
作者：
Okuma, Hidehiko;Hord, Jeffrey M.;Chandel, Ishita;Venzke, David;Anderson, Mary E.;Walimbe, Ameya S.;Joseph, Soumya;Gastel, Zeita;Hara, Yuji;Saito, Fumiaki;Matsumura, Kiichiro;Campbell, Kevin P.
肌营养不良聚糖 (DG) 需要大量的翻译后加工和 O-糖基化才能充当含有层粘连蛋白-G (LG) 结构域的细胞外基质 (ECM) 蛋白的受体。 Matriglycan 是一种由木糖 (Xyl) 和葡萄糖醛酸 (GlcA) 交替组成的细长多糖，与具有 LG 结构域的 ECM 蛋白以高亲和力结合，并且由 Like-乙酰氨基葡萄糖转移酶-1 (LARGE1) 在 α-肌营养不良聚糖 (α-DG) 上独特合成。 α-DG 的翻译后加工或 O-糖基化缺陷会导致基质聚糖变短，从而减小 α-DG 的大小并减少层粘连蛋白的结合，从而导致各种形式的肌营养不良症。此前，我们证明 LARGE1 需要蛋白 O-甘露糖激酶 (POMK) 在 α-DG (~150–250 kDa) 上生成全长基质聚糖 (Walimbe et al., 2020)。在这里，我们证明 LARGE1 只能在缺乏 DG N 末端 (α-DGN) 的小鼠骨骼肌中合成短的、非延长形式的基质聚糖，从而产生约 100–125 kDa 的 α-DG。这种较小形式的 α-DG 结合层粘连蛋白并维持特定的力，但不会阻止肌肉病理生理学，包括偏心收缩 (EC) 或神经肌肉接头异常后产生的力减少。总的来说，我们的研究表明，α-DGN 与 POMK 一样，是 LARGE1 将基质聚糖在 α-DG 上延伸至其完全成熟长度所必需的，从而防止肌肉病理生理学。
Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds with high affinity to ECM proteins with LG domains and is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1). Defects in the post-translational processing or O-glycosylation of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. Previously, we demonstrated that protein O-mannose kinase (POMK) is required for LARGE1 to generate full-length matriglycan on α-DG (~150–250 kDa) (Walimbe et al., 2020). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in an ~100–125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions (ECs) or abnormalities in the neuromuscular junctions. Collectively, our study demonstrates that α-DGN, like POMK, is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.
影响因子：
3.5
作者：
Kanagawa M;Nishimoto A;Chiyonobu T;Takeda S;Miyagoe-Suzuki Y;Wang F;Fujikake N;Taniguchi M;Lu Z;Tachikawa M;Nagai Y;Tashiro F;Miyazaki J;Tajima Y;Takeda S;Endo T;Kobayashi K;Campbell KP;Toda T
通讯作者：
Toda T