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  1. 020 学位論文
  2. 高エネルギー加速器科学研究科
  3. 13 物質構造科学専攻

STRUCTURAL STUDIES OF UBIQUITIN-BINDING ZINC FINGER DOMAINS IN THE NUCLEAR FACTOR KAPPA B PATHWAY

https://ir.soken.ac.jp/records/2166
https://ir.soken.ac.jp/records/2166
89585390-6cce-4b0e-9459-00c046acc277
名前 / ファイル ライセンス アクション
甲1380_要旨.pdf 要旨・審査要旨 (215.0 kB)
Item type 学位論文 / Thesis or Dissertation(1)
公開日 2011-06-03
タイトル
タイトル STRUCTURAL STUDIES OF UBIQUITIN-BINDING ZINC FINGER DOMAINS IN THE NUCLEAR FACTOR KAPPA B PATHWAY
タイトル
タイトル STRUCTURAL STUDIES OF UBIQUITIN-BINDING ZINC FINGER DOMAINS IN THE NUCLEAR FACTOR KAPPA B PATHWAY
言語 en
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_46ec
資源タイプ thesis
著者名 ROHAIM, AHMED MOHSEN AMIN

× ROHAIM, AHMED MOHSEN AMIN

ROHAIM, AHMED MOHSEN AMIN

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フリガナ ロハイム, アーメッド モーセン アミン

× ロハイム, アーメッド モーセン アミン

ロハイム, アーメッド モーセン アミン

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著者 ROHAIM, Ahmed Mohsen Amin

× ROHAIM, Ahmed Mohsen Amin

en ROHAIM, Ahmed Mohsen Amin

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学位授与機関
学位授与機関名 総合研究大学院大学
学位名
学位名 博士(理学)
学位記番号
内容記述タイプ Other
内容記述 総研大甲第1380号
研究科
値 高エネルギー加速器科学研究科
専攻
値 13 物質構造科学専攻
学位授与年月日
学位授与年月日 2010-09-30
学位授与年度
値 2010
要旨
内容記述タイプ Other
内容記述 Nuclear factor kappa B (NF-<small>K</small>B) is a key mediator of innate and adaptive immune
response. lncorrect regulation of NF-<small>K</small>B pathway has been linked to immune and
inflammatory disease as well as cancers. TAX1-binding protein 1 (TAX1BP1) is a
negative regulator of TNF-alpha- and IL-1β-induced NF-<small>K</small>B activation. TAX1BP1
comprises two C-terminal zinc finger domains that bind to mono- and polyubiquitin,
which are needed for TRAF6 (TNF-associated factor-6) or RIP1 (receptor interacting
protein-1) association followed by recruitment of A20 deubiquitinase (DUB), resulting in
NF-<small>K</small>B inhibition. TAX1BP1 acts as an adaptor protein, facilitating the process of de-
ubiquitination of target protein, resulting in the down regulation of the NF-<small>K</small>B pathway.

ln order to acquire a better understanding of the molecular interaction between the
ubiquitin zinc finger binding (UBZ) domain and ubiquitin, TAX1BP1 UBZ domain
interaction with mono-ubiquitin and different polyubiquitin chains were investigated in
this study. TAX1BP1 UBZ domain showed remarkable difference in terms of binding
affinities to monoubiquitin and polyubiquitin chains, as data reveals that there is a
significantly higher binding affinity to polyubiquitin (linear, lysine 63 and lysine 48
linked diubiquitin) chains over monoubiquitin.

The crystal structure of the C-terminal UBZ domains of TAX1BP1 in fusion with green
Fluorescence Protein (GFP) was solved at 2.8 Å resolution. The crystal structure shows
two tandem zinc fingers of the classical type C2H2, owing to the zinc coordinating
atoms, both having a β-β-α fold. Other members of the same C2H2 UBZ family are
proposed to bind ubiquitin exclusively through the α-helix in a manner similar to the
inverted ubiquitin-interacting motif (IUIM). Superposition of the α-helix of the UBZ
domain of TAX1BP1 to existing structural models indicates similar conformation of the
ubiquitin binding surface. However, through biochemical experiments, a model of
monoubiquitin/diubiquitin UBZ domain complex is proposed, indicating a new mode of
interaction between ubiquitin and UBZ domain of TAX1BP1, giving an insight to the
mechanism of ubiquitin recognition by TAX1BP1, and its function in the NF-<small>K</small>B
pathway.

Ubiquitin can be assembled in chains; the topology and signaling characteristics of these chains vary depending on the type of the linkage, adding an extra level of complexity in signaling. &quot;Linear&quot; polyubiquitin chain is a type of polyubiquitin assembly found recently, where ubiquitin moieties are threaded head to tail, and not like the classical lysine linked polyubiquitin chains. Linear polyubiquitin plays an indispensible role in the NF-<small>K</small>B pathway. The crystal structure of linear diubiquitin was solved at 1.9 Å resolution,giving a closer understanding of the mechanism of interactions. It is shown that linear diubiquitin can acquire more than one conformation in solution to meet the surface and chemical complementarities of the cognate domains, and also emphasizing the importance of the linker region, between the two ubiquitin moieties which plays a pivotal role in the process of specific recognition.
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