The mechanisms of conformational regulation of ErbB receptors by N-glycans

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07339
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Sapporo Medical University
• Principal Investigator: Takahashi Motoko 札幌医科大学, 医学部, 教授 (00303941)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 糖鎖 / 増殖因子受容体 / ErbB / EGFR

Outline of Final Research Achievements

The functional regulation and conformational regulation of growth factor receptors ErbB by N-glycans were examined. N-glycans on EGFR N420, ErbB3 N418, ErbB4 N333 were involved in receptor activation. We examined the site-specific glycosylation status and glycan structures of ErbBs and found that their glycan occupancies were 100% and they were a complex type with little fucose. The signaling inhibitory effects were increased in sEGFR N420Q and sErbB3 N418Q mutants. Although the crystal structure of sErbB3 was not altered by the deletion of N-glycan on N418 by N418Q mutation, the melting temperature of sErbB3 N418Q decreased compared to the wild type, suggesting that this N-glycan contributes to the conformational stability of sErbB3. Taken together, our results suggested that N-glycan on N418 of sErbB3 is involved in the stabilization of structure and that deletion of this glycan increases the structural flexibility which results in facilitation of dimer formation.

Free Research Field

生化学、糖鎖生物学

Academic Significance and Societal Importance of the Research Achievements

ErbBはがん治療のターゲットであり、その制御機構を明らかにすることは社会的にも重要である。研究代表者は糖鎖によるErbBの制御について調べているが、その根本的なメカニズムは「糖鎖による受容体の物性制御」にあると考えている。本研究の結果、特定の糖鎖がErbBの構造変化に関与していることが示唆された。同時に、それらの糖鎖に共通する特徴も見出した。以上の結果は糖鎖の機能の解明につながる可能性がある。