Department of Physics, University of Helsinki, P.O. Box 64, 00014, Helsinki, Finland.
Computational Physics Laboratory, Tampere University, PO Box 692, 33014, Tampere, Finland.
Sci Rep. 2021 Mar 4;11(1):5239. doi: 10.1038/s41598-021-84569-z.
While DNA encodes protein structure, glycans provide a complementary layer of information to protein function. As a prime example of the significance of glycans, the ability of the cell surface receptor CD44 to bind its ligand, hyaluronan, is modulated by N-glycosylation. However, the details of this modulation remain unclear. Based on atomistic simulations and NMR, we provide evidence that CD44 has multiple distinct binding sites for hyaluronan, and that N-glycosylation modulates their respective roles. We find that non-glycosylated CD44 favors the canonical sub-micromolar binding site, while glycosylated CD44 binds hyaluronan with an entirely different micromolar binding site. Our findings show (for the first time) how glycosylation can alter receptor affinity by shielding specific regions of the host protein, thereby promoting weaker binding modes. The mechanism revealed in this work emphasizes the importance of glycosylation in protein function and poses a challenge for protein structure determination where glycosylation is usually neglected.
虽然 DNA 编码蛋白质结构，但糖链为蛋白质功能提供了一个互补的信息层。糖链的重要性的一个主要例子是，细胞表面受体 CD44 结合其配体透明质酸的能力受 N-糖基化调节。然而，这种调节的细节仍不清楚。基于原子模拟和 NMR，我们提供了证据表明 CD44 有多个不同的透明质酸结合位点，并且 N-糖基化调节它们各自的作用。我们发现，未糖基化的 CD44 有利于经典的亚毫摩尔结合位点，而糖基化的 CD44 则以完全不同的毫摩尔结合位点结合透明质酸。我们的发现首次表明，糖基化如何通过屏蔽宿主蛋白的特定区域来改变受体亲和力，从而促进较弱的结合模式。这项工作揭示的机制强调了糖基化在蛋白质功能中的重要性，并对通常被忽视糖基化的蛋白质结构测定提出了挑战。
