Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction.
Means of self-preservation: how an intrinsically disordered ubiquitin-protein ligase averts self-destruction.
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DOI：
10.1091/mbc.e12-11-0811
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发表时间：
2013-04
影响因子：
3.3
通讯作者：
Gardner RG
中科院分区：
文献类型：
--
作者：
Fredrickson EK;Clowes Candadai SV;Tam CH;Gardner RG
泛素蛋白连接酶（E3s）通常处于自身泛素化的危险位置，介导其自身的破坏。内在无序的E3 San1通过最小化其无序区域的赖氨酸残基和疏水延伸来防止其自身的自泛素化和降解。泛素蛋白连接酶（E3s）使蛋白酶体降解的底物泛素化，由于与带电的泛素偶联酶（E2）相互作用，通常处于泛素化的位置。这可以介导E3的蛋白酶体降解。许多E3s已经进化出避免自身泛素化的方法，包括伴侣或底物结合的保护、预防性修饰和泛素化的去泛素化酶逆转。在这里，我们描述了在探索酵母中错误折叠的核蛋白泛素化用于蛋白酶体降解的San1时发现的E3自我保护的另一种适应。San1的底物结合区N端和c端到RING结构域高度无序。在顺式中，如果这些柔性区域靠近E2，则可能发生自泛化。San1通过在其无序区域不含赖氨酸来防止这种情况；因此，用于泛素附着的典型残基已被选择性地消除。San1的靶底物失去了原有的结构，暴露出疏水性。为了避免反式自泛素化，San1在其无序区域具有很少集中的疏水性，因此San1在错误折叠底物中识别的特征也被选择性地消除了。总的来说，San1中关键残基的存在已经被进化地最小化，以避免在顺式或反式中自毁。我们的工作扩展了E3s保护自己免受自我克隆的方式。
Ubiquitin-protein ligases (E3s) are often in the precarious position of ubiquitinating themselves, mediating their own destruction. The intrinsically disordered E3 San1 prevents its own autoubiquitination and degradation by minimizing Lys residues and hydrophobic stretches in its disordered regions. Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3’s proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination, including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate-binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions; thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1’s target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, and thus the that feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways in which E3s protect themselves from autoubiquitination.