8H24

Leucine-rich alpha-2-glycoprotein 1

8H24 の概要

• エントリーDOI: 10.2210/pdb8h24/pdb
• 分子名称: Leucine-rich alpha-2-glycoprotein, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: angiogenesis, neurite outgrowth, soluble ligand, secreted glycoprotein, unknown function
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39197.67

構造登録者

Won, S.Y.,Park, B.S.,Lee, D.S.,Kim, H.M.,Han, A.,Yang, J. (登録日: 2022-10-04, 公開日: 2023-08-23, 最終更新日: 2024-10-23)

主引用文献

Yang, J.,Yin, G.N.,Kim, D.K.,Han, A.R.,Lee, D.S.,Min, K.W.,Fu, Y.,Yun, J.,Suh, J.K.,Ryu, J.K.,Kim, H.M.
Crystal structure of LRG1 and the functional significance of LRG1 glycan for LPHN2 activation.
Exp.Mol.Med., 55:1013-1022, 2023

PubMed Abstract: The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFβ signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analyses found that the deglycosylation of LRG1, particularly the removal of glycans on N325, is critical for the high-affinity binding of LRG1 to LPHN2 and thus promotes LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, the intracavernous administration of deglycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1 glycans as molecular switches that can tune the range of LRG1's cellular functions, particularly the LRG1/LPHN2 signaling axis.

PubMed: 37121976
DOI: 10.1038/s12276-023-00992-4

実験手法

X-RAY DIFFRACTION (2.45 Å)