Functional and structural deficiencies of Gemin5 variants associated with neurological disorders.
Functional and structural deficiencies of Gemin5 variants associated with neurological disorders.
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DOI：
10.26508/lsa.202201403
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发表时间：
2022-07
影响因子：
4.4
通讯作者：
Martinez-Salas E
中科院分区：
文献类型：
--
作者：
Francisco-Velilla R;Embarc-Buh A;Del Caño-Ochoa F;Abellan S;Vilar M;Alvarez S;Fernandez-Jaen A;Kour S;Rajan DS;Pandey UB;Ramón-Maiques S;Martinez-Salas E
Gemin 5临床变异扰乱二聚化模块和非经典RNA结合位点损害寡聚化、RNA-蛋白质相互作用网络、核糖体缔合和蛋白质稳定性。RNA结合蛋白的功能障碍通常与多种人类疾病有关，特别是与神经系统疾病有关。Gemin 5是运动神经元存活复合体（SMN）的成员，是一种核糖体结合蛋白和翻译重编程因子。最近，致病性突变Gemin 5已被报道，但这些变异的功能后果仍然难以捉摸。在这里，我们报告的功能和结构缺陷与复合杂合性变异内发现的神经发育障碍患者的Gemin 5基因。这些临床变异体位于Gemin 5的关键结构域，即三肽重复序列（TPR）样二聚化模块和非经典RNA结合位点1（RBS 1）。我们发现，TPR样的变体破坏蛋白质二聚化，而RBS 1的变体赋予蛋白质的不稳定性。所有突变体在与参与翻译和RNA驱动途径的蛋白质网络的相互作用中都是有缺陷的。重要的是，TPR样变体不能与天然核糖体结合，阻碍了其参与翻译控制并与野生型蛋白建立功能差异。我们的研究提供了深入了解与Gemin 5蛋白功能障碍相关的疾病的分子基础。
Gemin5 clinical variants perturbing the dimerization module and the noncanonical RNA-binding site impair oligomerization, RNA–protein interaction networks, ribosome association, and protein stability. Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)–like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
影响因子：
10.5
作者：
Mourelatos, Z;Dostie, J;Dreyfuss, G
通讯作者：
Dreyfuss, G
影响因子：
4.1
作者：
Embarc-Buh A;Francisco-Velilla R;Camero S;Pérez-Cañadillas JM;Martínez-Salas E
通讯作者：
Martínez-Salas E
DOI：
10.1186/s12964-016-0132-3
发表时间：
2016-04-06
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Järvelin AI;Noerenberg M;Davis I;Castello A
通讯作者：
Castello A
影响因子：
7.2
作者：
Kastner, Berthold;Will, Cindy L.;Luehrmann, Reinhard
通讯作者：
Luehrmann, Reinhard