Department of Biochemistry, McGill University, Montreal, QC H3G 0B1, Canada.
Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0C7, Canada.
Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2203518119. doi: 10.1073/pnas.2203518119. Epub 2022 Aug 8.
The mannose-6-phosphate (M6P) pathway is responsible for the transport of hydrolytic enzymes to lysosomes. N-acetylglucosamine-1-phosphotransferase (GNPT) catalyzes the first step of tagging these hydrolases with M6P, which when recognized by receptors in the Golgi diverts them to lysosomes. Genetic defects in the GNPT subunits, GNPTAB and GNPTG, cause the lysosomal storage diseases mucolipidosis types II and III. To better understand its function, we determined partial three-dimensional structures of the GNPT complex. The catalytic domain contains a deep cavity for binding of uridine diphosphate--acetylglucosamine, and the surrounding residues point to a one-step transfer mechanism. An isolated structure of the gamma subunit of GNPT reveals that it can bind to mannose-containing glycans in different configurations, suggesting that it may play a role in directing glycans into the active site. These findings may facilitate the development of therapies for lysosomal storage diseases.
甘露糖-6-磷酸（M6P）途径负责将水解酶运输到溶酶体。N-乙酰葡萄糖胺-1-磷酸转移酶（GNPT）催化这些水解酶与 M6P 结合的第一步，当被高尔基复合体中的受体识别时，它们会被引导到溶酶体。GNPT 亚基 GNPTAB 和 GNPTG 的遗传缺陷会导致溶酶体贮积症 II 型和 III 型粘脂贮积症。为了更好地了解其功能，我们确定了 GNPT 复合物的部分三维结构。催化结构域包含一个用于结合尿苷二磷酸-乙酰葡萄糖胺的深腔，周围的残基指向一步转移机制。GNPT 的γ亚基的分离结构表明，它可以以不同的构象与含有甘露糖的聚糖结合，这表明它可能在将聚糖引导到活性部位方面发挥作用。这些发现可能有助于开发溶酶体贮积症的治疗方法。
