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Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9.
Structure ( IF 4.4 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.str.2020.08.002
Alice J Bochel 1 , Christopher Williams 2 , Airlie J McCoy 3 , Hans-Jürgen Hoppe 4 , Ashley J Winter 1 , Ryan D Nicholls 1 , Karl Harlos 5 , E Yvonne Jones 5 , Imre Berger 6 , A Bassim Hassan 7 , Matthew P Crump 2
Affiliation  

The cation-independent mannose 6-phosphate (M6P)/Insulin-like growth factor-2 receptor (CI-MPR/IGF2R) is an ∼300 kDa transmembrane protein responsible for trafficking M6P-tagged lysosomal hydrolases and internalizing IGF2. The extracellular region of the CI-MPR has 15 homologous domains, including M6P-binding domains (D) 3, 5, 9, and 15 and IGF2-binding domain 11. We have focused on solving the first structures of human D7–10 within two multi-domain constructs, D9–10 and D7–11, and provide the first high-resolution description of the high-affinity M6P-binding D9. Moreover, D9 stabilizes a well-defined hub formed by D7–11 whereby two penta-domains intertwine to form a dimeric helical-type coil via an N-glycan bridge on D9. Remarkably the D7–11 structure matches an IGF2-bound state of the receptor, suggesting this may be an intrinsically stable conformation at neutral pH. Interdomain clusters of histidine and proline residues may impart receptor rigidity and play a role in structural transitions at low pH.



中文翻译:

人类阳离子非依赖性甘露糖 6-磷酸/IGF2 受体结构域 7-11 的结构揭示了结构域 9 的甘露糖 6-磷酸结合位点。

不依赖阳离子的 6-磷酸甘露糖 (M6P)/胰岛素样生长因子 2 受体 (CI-MPR/IGF2R) 是一种约 300 kDa 的跨膜蛋白,负责运输 M6P 标记的溶酶体水解酶和内化 IGF2。CI-MPR 的胞外区域有 15 个同源结构域,包括 M6P 结合结构域 (D) 3、5、9 和 15 和 IGF2 结合结构域 11。我们专注于解决人类 D7-10 的第一个结构两个多域结构,D9-10 和 D7-11,并提供了高亲和力 M6P 结合 D9 的第一个高分辨率描述。此外,D9 稳定了由 D7-11 形成的明确定义的枢纽,其中两个五域通过 D9 上的 N-聚糖桥交织形成二聚螺旋型线圈。值得注意的是,D7-11 结构与受体的 IGF2 结合状态相匹配,表明这可能是在中性 pH 值下本质上稳定的构象。组氨酸和脯氨酸残基的域间簇可能赋予受体刚性并在低 pH 下的结构转变中发挥作用。

更新日期:2020-09-01
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