Structure of LRRK1 and mechanisms of autoinhibition and activation.
Structure of LRRK1 and mechanisms of autoinhibition and activation.
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DOI：
10.1038/s41594-023-01109-1
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发表时间：
2023-11
影响因子：
16.8
通讯作者：
Leschziner, Andres E.
中科院分区：
文献类型：
--
作者：
Reimer, Janice M.;Dickey, Andrea M.;Lin, Yu Xuan;Abrisch, Robert G.;Mathea, Sebastian;Chatterjee, Deep;Fay, Elizabeth J.;Knapp, Stefan;Daugherty, Matthew D.;Reck-Peterson, Samara L.;Leschziner, Andres E.
富含亮氨酸重复激酶1和2（LRRK 1和LRRK 2）是人类ROCO蛋白家族中的同源物。尽管它们有共同的结构域结构并参与细胞内运输，但它们的疾病关联是惊人的不同：LRRK 2参与家族性帕金森病，而LRRK 1与骨骼疾病有关。此外，LRRK 2中的帕金森病相关突变通常是常染色体显性功能获得性突变，而LRRK 1中的突变是常染色体隐性功能丧失性突变。在这里，为了理解这些差异，我们解决了单体和二聚体形式的LRRK 1的cryo-EM结构。两者都不同于相应的LRRK 2结构。与作为单体的空间自抑制的LRRK 2不同，LRRK 1以二聚体依赖性方式空间自抑制。LRRK 1具有额外水平的自身抑制，其防止激酶的活化，并且在LRRK 2中不存在。最后，我们将LRRK 1和LRRK 2的结构特征放在LRRK家族蛋白质进化的背景下。Reimer等人使用cryo-EM和细胞分析来揭示区分LRRK 1和LRRK 2的结构和调控特征，并将这些特征置于LRRK家族蛋白质进化的背景下。
Leucine Rich Repeat Kinase 1 and 2 (LRRK1 and LRRK2) are homologs in the ROCO family of proteins in humans. Despite their shared domain architecture and involvement in intracellular trafficking, their disease associations are strikingly different: LRRK2 is involved in familial Parkinson’s disease while LRRK1 is linked to bone diseases. Furthermore, Parkinson’s disease-linked mutations in LRRK2 are typically autosomal dominant gain-of-function while those in LRRK1 are autosomal recessive loss-of-function. Here, to understand these differences, we solved cryo-EM structures of LRRK1 in its monomeric and dimeric forms. Both differ from the corresponding LRRK2 structures. Unlike LRRK2, which is sterically autoinhibited as a monomer, LRRK1 is sterically autoinhibited in a dimer-dependent manner. LRRK1 has an additional level of autoinhibition that prevents activation of the kinase and is absent in LRRK2. Finally, we place the structural signatures of LRRK1 and LRRK2 in the context of the evolution of the LRRK family of proteins. Reimer et al. used cryo-EM and cellular assays to reveal the structural and regulatory features that distinguish LRRK1 from LRRK2, and placed these features in the context of the evolution of the LRRK family of proteins.
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影响因子：
5.6
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1042/bcj20200937
发表时间：
2021-02-12
期刊：
The Biochemical journal
影响因子：
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作者：
Malik AU;Karapetsas A;Nirujogi RS;Mathea S;Chatterjee D;Pal P;Lis P;Taylor M;Purlyte E;Gourlay R;Dorward M;Weidlich S;Toth R;Polinski NK;Knapp S;Tonelli F;Alessi DR
通讯作者：
Alessi DR
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W
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