Structural insights into ubiquitin phosphorylation by PINK1.
Structural insights into ubiquitin phosphorylation by PINK1.
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DOI：
10.1038/s41598-018-28656-8
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发表时间：
2018-07-10
影响因子：
4.6
通讯作者：
Fukai S
中科院分区：
文献类型：
--
作者：
Okatsu K;Sato Y;Yamano K;Matsuda N;Negishi L;Takahashi A;Yamagata A;Goto-Ito S;Mishima M;Ito Y;Oka T;Tanaka K;Fukai S
PTEN诱导的推定激酶1（PINK 1）和E3泛素（Ub）连接酶parkin的突变可引起家族性帕金森综合征。这两种蛋白质对于受损线粒体的泛素化和随后的降解是必不可少的。PINK 1磷酸化Ub的Ser 65和parkin的Ub-like（UBL）结构域以变构地解除parkin的自身抑制。为了了解PINK 1特异性磷酸化Ub/UBL的结构机制，我们确定了赤拟谷盗PINK 1激酶结构域（TcPINK 1）与不可水解的ATP类似物复合物的晶体结构，分辨率为2.5 nm。TcPINK 1由具有PINK 1特异性延伸的N-和C-末端叶组成。ATP类似物结合在N-和C-末端叶之间的裂缝中。ATP类似物的腺嘌呤环结合到疏水口袋，而ATP类似物的三磷酸基团和两个配位的Mg离子与催化性亲水残基相互作用。与蛋白激酶A和C（PKA和PKC，分别）的比较揭示了一个假定的Ub/UBL结合沟，这是更广泛的比PKA或PKC的肽结合沟，以适应球状头部的Ub或UBL。进一步的交联分析表明Ub的PINK 1相互作用表面。结构指导的突变分析支持目前PINK 1结构分析的结果。
Mutations of PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin (Ub) ligase parkin can cause familial parkinsonism. These two proteins are essential for ubiquitylation of damaged mitochondria and subsequent degradation. PINK1 phosphorylates Ser65 of Ub and the Ub-like (UBL) domain of parkin to allosterically relieve the autoinhibition of parkin. To understand the structural mechanism of the Ub/UBL-specific phosphorylation by PINK1, we determined the crystal structure of Tribolium castaneum PINK1 kinase domain (TcPINK1) in complex with a nonhydrolyzable ATP analogue at 2.5 Å resolution. TcPINK1 consists of the N- and C-terminal lobes with the PINK1-specific extension. The ATP analogue is bound in the cleft between the N- and C-terminal lobes. The adenine ring of the ATP analogue is bound to a hydrophobic pocket, whereas the triphosphate group of the ATP analogue and two coordinated Mg ions interact with the catalytic hydrophilic residues. Comparison with protein kinases A and C (PKA and PKC, respectively) unveils a putative Ub/UBL-binding groove, which is wider than the peptide-binding groove of PKA or PKC to accommodate the globular head of Ub or UBL. Further crosslinking analyses suggested a PINK1-interacting surface of Ub. Structure-guided mutational analyses support the findings from the present structural analysis of PINK1.
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影响因子：
7.7
作者：
Kazlauskaite A;Martínez-Torres RJ;Wilkie S;Kumar A;Peltier J;Gonzalez A;Johnson C;Zhang J;Hope AG;Peggie M;Trost M;van Aalten DM;Alessi DR;Prescott AR;Knebel A;Walden H;Muqit MM
通讯作者：
Muqit MM
影响因子：
15.1
作者：
Ando M;Fiesel FC;Hudec R;Caulfield TR;Ogaki K;Górka-Skoczylas P;Koziorowski D;Friedman A;Chen L;Dawson VL;Dawson TM;Bu G;Ross OA;Wszolek ZK;Springer W
通讯作者：
Springer W
影响因子：
64.5
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
通讯作者：
Kuriyan, John
DOI：
10.1073/pnas.1417571112
发表时间：
2015-03-03
影响因子：
11.1
作者：
Alexa, Anita;Gogl, Gergo;Remenyi, Attila
通讯作者：
Remenyi, Attila
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K