Molecular dynamics reveal the essential role of linker motions in the function of cullin-RING E3 ligases.
Molecular dynamics reveal the essential role of linker motions in the function of cullin-RING E3 ligases.
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DOI：
10.1016/j.jmb.2010.01.022
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发表时间：
2010-03-12
影响因子：
5.6
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Liu J;Nussinov R
Tagging proteins by polyubiquitin is a key step in protein degradation. Cullin-RING E3 ubiquitin ligases (CRLs) facilitate ubiquitin transfer from the E2 conjugating enzyme to the substrate; yet, crystallography indicates a large distance between the E2 and the substrate, raising the question of how this distance is bridged in the ubiquitin transfer reaction. Here, we demonstrate that the linker motions in the substrate binding proteins can allosterically shorten this distance to facilitate this crucial ubiquitin transfer step, and increase this distance to allow polyubiquitination. We performed molecular dynamics simulations for five substrate binding proteins, Skp2, Fbw7, β-TrCP1, Cdc4, and pVHL, in two forms: bound to their substrates, and bound to both substrate and adaptor. The adaptor connects the substrate binding proteins to the cullin. In the bound-to-both forms of all cases, we observed rotations of the substrate binding domain, shortening the gap between the tip of the substrate peptide and the E2 active site by 7~12Å compared to the crystal structures. Overall, together with our earlier simulations of the unbound and the bound-to-adaptor forms, the emerging picture is that the maximum 51~73Å distance between the substrate binding domain and the E2 active site in the modeled unbound forms of these five proteins shrinks to a minimum of 39~49Å in the bound-to-both forms. This large distance range, the result of allosterically-controlled linker motions, facilitates the ubiquitin transfer and polyubiquitination, and as such argues that the cullin-RING E3 ubiquitin ligase is under conformational control. We further observed that substrate binding proteins with multiple substrate acceptor lysines have larger distance range between the substrate and the E2 as compared to β-TrCP1, with only one acceptor lysine.
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DOI：
10.1016/j.str.2009.06.008
发表时间：
2009-08-12
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
del Sol A;Tsai CJ;Ma B;Nussinov R
通讯作者：
Nussinov R
Cullin环E3连接酶机械中泛素化的机制：底物方向的构象控制。
影响因子：
4.3
作者：
Liu J;Nussinov R
通讯作者：
Nussinov R
影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
2.9
作者：
Banavali, Nilesh K.;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
16
作者：
Hao, B;Zheng, N;Pavletich, NP
通讯作者：
Pavletich, NP