UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids.
UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids.
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DOI：
10.1038/nature09966
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发表时间：
2011-06-02
期刊：
影响因子：
64.8
通讯作者：
Klevit, Rachel E.
中科院分区：
文献类型：
--
作者：
Wenzel, Dawn M.;Lissounov, Alexei;Brzovic, Peter S.;Klevit, Rachel E.
虽然泛素缀合酶（E2）和泛素连接酶（E3）之间的功能相互作用在泛素（Ub）信号传导中是必不可少的，但是定义活性E2-E3对的标准还没有很好地建立。人E2 UbcH 7（Ube 2L 3）对HECT型E3表现出广泛的特异性，但尽管形成特异性复合物，但在体外通常不能与RING E3起作用。非活性UbcH 7/RING复合物与活性UbcH 5/RING复合物的结构比较没有发现明显的差异，这突出了我们对Ub转移理解的差距。我们发现，不像许多E2的转移Ub与RINGs，UbcH 7缺乏内在的，E3独立的反应与赖氨酸，解释其偏好HECTs。尽管缺乏赖氨酸反应性，但UbcH 7表现出与E3的RING-中间环（RBR）家族的活性，所述RBR家族包括帕金和阿里阿德涅的人类同源物（HHARI）。在所有真核生物中发现，RBRs调节翻译和免疫信号传导等过程。RBR含有典型的C3 HC 4型RING，随后是两个保守的富含Cys/His的Zn 2+结合结构域，In-Between-RING（IBR）和RING 2结构域，它们共同定义了E3家族。在这里，我们表明RBRs的功能类似于RING/HECT杂交体：它们通过RING结构域结合E2，但通过专性硫酯连接的Ub（表示为“~ Ub”）转移Ub，需要RING 2中的保守半胱氨酸残基。我们的研究结果定义了UbcH 7，E2参与细胞增殖和免疫功能的E3的功能干部，并提出了一个新的机制，为整个类的E3。
Although the functional interaction between ubiquitin conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signaling, the criteria that define an active E2–E3 pair are not well-established. The human E2 UbcH7 (Ube2L3) shows broad specificity for HECT-type E3s, but often fails to function with RING E3s in vitro despite forming specific complexes. Structural comparisons of inactive UbcH7/RING complexes with active UbcH5/RING complexes reveal no defining differences, highlighting a gap in our understanding of Ub transfer. We show that, unlike many E2s that transfer Ub with RINGs, UbcH7 lacks intrinsic, E3-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UbcH7 exhibits activity with the RING-In Between-RING (RBR) family of E3s that includes Parkin and human homologue of ariadne (HHARI). Found in all eukaryotes, RBRs regulate processes such as translation and immune signaling. RBRs contain a canonical C3HC4-type RING, followed by two conserved Cys/His-rich Zn2+-binding domains, In-Between-RING (IBR) and RING2 domains, which together define this E3 family. Here we show that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer Ub through an obligate thioester-linked Ub (denoted ‘~Ub’), requiring a conserved cysteine residue in RING2. Our results define the functional cadre of E3s for UbcH7, an E2 involved in cell proliferation and immune function, and suggest a novel mechanism for an entire class of E3s.
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