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The non-glycosylated N-terminal domain of human thrombopoietin is a molten globule under native conditions
https://repo.qst.go.jp/records/75928
https://repo.qst.go.jp/records/7592862b984e8-db80-42d8-8c95-935100ebe5c7
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-07-20 | |||||
| タイトル | ||||||
| タイトル | The non-glycosylated N-terminal domain of human thrombopoietin is a molten globule under native conditions | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Arai, Shigeki
× Arai, Shigeki× Shibazaki, Chie× Adachi, Motoyasu× Maeda, Yoshitake× Tahara, Tomoyuki× Kato, Takashi× Miyazaki, Hiroshi× Kuroki, Ryota× Arai, Shigeki× Shibazaki, Chie× Adachi, Motoyasu |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Human thrombopoietin (hTPO) is a primary hematopoietic growth factor that regulates megakaryocytopoiesis and platelet production. The non-glycosylated form of 1–163 residues of hTPO (hTPO163) including the N-terminal active site domain (1–153 residues) is a candidate for treating thrombocytopenia. However, the autoantigenicity level of hTPO163 is higher than that of the full-length glycosylated hTPO (ghTPO332). In order to clarify the structural and physicochemical properties of hTPO163, circular dichroism (CD) and differential scanning calorimetry (DSC) analyses were performed. CD analysis indicated that hTPO163 undergoes an induced-fit conformational change (+19.0% for helix and −16.7% for β-strand) upon binding to the neutralising antibody TN1 in a manner similar to the coupled folding and binding mechanism. Moreover, DSC analysis showed that the thermal transition process of hTPO163 is a multi-state transition; hTPO163 is thermally stabilized upon receptor (c-Mpl) binding, as indicated with raising the mid-point (Tm) temperature of the transition by at least +9.5 K. The conformational variability and stability of hTPO163 indicate that hTPO163 exists as a molten globule under native conditions, which may enable the induced-fit conformational change according to the type of ligands (antibodies and receptor). Additionally, CD and computational analyses indicated that the C-terminal domain (154–332 residues) and glycosylation assists the folding of the N-terminal domain. These observations suggest that the antibody affinity and autoantigenicity of hTPO163 might be reduced, if the conformational variability of hTPO163 is restricted by mutation and/or by the addition of C-terminal domain with glycosylation to keep its conformation suitable for the c-Mpl recognition. | |||||
| 書誌情報 |
The FEBS Journal 巻 286, 号 9, p. 1717-1733, 発行日 2019-01 |
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| 出版者 | ||||||
| 出版者 | FEBS PRESS | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 1742-464X | |||||
| PubMed番号 | ||||||
| 識別子タイプ | PMID | |||||
| 関連識別子 | 30675759 | |||||
| DOI | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | 10.1111/febs.14765 | |||||
| 関連サイト | ||||||
| 識別子タイプ | URI | |||||
| 関連識別子 | https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.14765 | |||||
