Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark.
J Biol Chem. 2011 Sep 16;286(37):32736-48. doi: 10.1074/jbc.M111.266692. Epub 2011 Jul 18.
Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events and in several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, the function of which is poorly known. The endocytic collagen receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role in matrix remodeling through its ability to internalize collagen for lysosomal degradation. uPARAP/Endo180 is a member of the mannose receptor protein family. These proteins all include a fibronectin type II domain and a series of C-type lectin-like domains, of which only a minor part possess carbohydrate recognition activity. At least two of the family members, uPARAP/Endo180 and the mannose receptor, interact with collagens. The molecular basis for this interaction is known to involve the fibronectin type II domain but nothing is known about the function of the lectin domains in this respect. In this study, we have investigated a possible role of the single active lectin domain of uPARAP/Endo180 in the interaction with collagens. By expressing truncated recombinant uPARAP/Endo180 proteins and analyzing their interaction with collagens with high and low levels of glycosylation we demonstrated that this lectin domain interacts directly with glycosylated collagens. This interaction is functionally important because it was found to modulate the endocytic efficiency of the receptor toward highly glycosylated collagens such as basement membrane collagen IV. Surprisingly, this property was not shared by the mannose receptor, which internalized glycosylated collagens independently of its lectin function. This role of modulating its uptake efficiency by a specific receptor is a previously unrecognized function of collagen glycosylation.
胶原构成了细胞外间质和基底膜中最丰富的成分。胶原重塑是许多正常生理事件和几种病理状况中的关键过程。一些胶原亚型含有特定的碳水化合物侧链，其功能知之甚少。内吞胶原受体尿激酶型纤溶酶原激活物受体相关蛋白（uPARAP）/Endo180 通过内化胶原进行溶酶体降解，在基质重塑中发挥重要作用。uPARAP/Endo180 是甘露糖受体蛋白家族的成员。这些蛋白都包含一个纤维连接蛋白 II 结构域和一系列 C 型凝集素样结构域，其中只有一小部分具有碳水化合物识别活性。至少有两个家族成员，uPARAP/Endo180 和甘露糖受体，与胶原相互作用。这种相互作用的分子基础已知涉及纤维连接蛋白 II 结构域，但在这方面，关于凝集素结构域的功能一无所知。在这项研究中，我们研究了 uPARAP/Endo180 中单个活性凝集素结构域在与胶原相互作用中的可能作用。通过表达截断的重组 uPARAP/Endo180 蛋白，并分析其与高糖基化和低糖基化胶原的相互作用，我们证明了该凝集素结构域与糖基化胶原直接相互作用。这种相互作用具有功能重要性，因为它被发现调节了受体对高度糖基化胶原（如基底膜胶原 IV）的内吞效率。令人惊讶的是，这种特性并不为甘露糖受体所共有，甘露糖受体独立于其凝集素功能内化糖基化胶原。这种通过特定受体调节其摄取效率的作用是胶原糖基化的一个以前未被认识的功能。
