Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands.
Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands.
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作者：
J. Gliemann
LDL受体家族成员是由重复的蛋白质模块组成的内吞受体，包括配体结合LDL受体A类（LA）重复序列的簇。大的（约600 kDa）成员LRP和巨蛋白结合许多结构上不相关的，往往是复杂的配体在不同的组合网站。LRP在广泛但有限的细胞类型中表达，包括肝细胞、巨噬细胞、平滑肌细胞和CNS神经元。巨蛋白在各种上皮细胞中表达，包括近端肾小管、肠和室管膜细胞。这两种受体共享大量配体，因此它们在体内的功能在很大程度上由它们的表达模式决定。例如，两种受体都可以内吞脂蛋白，但这种功能似乎主要与LRP相关。此外，LRP通过配体介导的内化，随后使裸尿激酶受体返回细胞表面，帮助调节细胞表面上的尿激酶受体表达。这两种受体也具有特殊功能。LRP对α 2-巨球蛋白-蛋白酶复合物的结合具有特异性，并提供复合物和与复合物相关的肽（例如细胞因子）的清除。Megalin在维生素B12体内平衡中具有重要功能，因为它特异性地介导维生素B12-转钴胺素复合物的摄取，并帮助在肾脏中建立维生素的储存库。此外，巨蛋白与最近发现的B12-内因子复合物受体cubilin结合，从而提供了膳食维生素B12的吸收机制。最后，巨蛋白特异性介导载脂蛋白J/丛生蛋白的摄取，载脂蛋白J/丛生蛋白是与阿尔茨海默病有关的Abeta肽的结合蛋白。属于不同生理系统的多个复杂配体的结合为旨在阐明LRP和megalin在疾病机制中的作用的未来研究提供了挑战。
The LDL receptor family members are endocytic receptors composed of repeated protein modules, including clusters of ligand binding LDL receptor class A (LA) repeats. The large (approximately 600 kDa) members LRP and megalin bind numerous structurally unrelated and often complex ligands at different combinations of sites. LRP is expressed in a wide but restricted set of cell types including hepatocytes, macrophages, smooth muscle cells, and neurons of the CNS. Megalin is expressed in various epithelia including proximal kidney tubules, intestine, and ependymal cells. The two receptors share a multitude of ligands, and their function in vivo is therefore to a large extent determined by their expression pattern. For example, both receptors can endocytose lipoproteins, but this function appears mainly relevant for LRP. In addition, LRP helps regulating urokinase receptor expression on the cell surface via ligand-mediated internalization followed by return of the naked urokinase receptor to the cell surface. Both receptors also have specialist functions. LRP is specific for binding of alpha2-macroglobulin-proteinase complexes and provides clearance of the complexes and of peptides, e.g. cytokines, associated with the complex. Megalin has important functions in vitamin B12 homeostasis since it specifically mediates uptake of the vitamin B12-transcobalamin complex and helps building a storage pool for the vitamin in the kidneys. Moreover, megalin binds cubilin, the recently identified receptor for B12-intrinsic factor complex, thus providing a mechanism for uptake of dietary vitamin B12. Finally, megalin specifically mediates uptake of apolipoprotein J/clusterin, a binding protein for the Abeta peptide implicated in Alzheimer's disease. The binding of multiple complex ligands that belong to distinct physiological systems provides a challenge in future studies aiming at elucidating the role of LRP and megalin in disease mechanisms.