Kinetics of recruitment and allosteric activation of ARHGEF25 isoforms by the heterotrimeric G-protein Gαq.
Kinetics of recruitment and allosteric activation of ARHGEF25 isoforms by the heterotrimeric G-protein Gαq.
复制标题
DOI：
10.1038/srep36825
复制
发表时间：
2016-11-11
影响因子：
4.6
通讯作者：
Goedhart J
中科院分区：
文献类型：
--
作者：
van Unen J;Yin T;Wu YI;Mastop M;Gadella TW Jr;Goedhart J
Rho GTPases 是真核细胞骨架的主要调节因子。 Rho GTP 酶的激活受 Rho 鸟嘌呤核苷酸交换因子 (GEF) 控制。 ARHGEF25 基因产生三种 RhoGEF 亚型； p63RhoGEF580、GEFT 和最近发现的 619 个氨基酸的更长异构体 (p63RhoGEF619)。 p63RhoGEF580和p63RhoGEF619的亚细胞分布在未刺激的细胞中显着不同，p63RhoGEF580位于质膜，而p63RhoGEF619局限于细胞质。有趣的是，我们发现在刺激 Gαq 偶联的 GPCR 后，P63RhoGEF580 和 p63RhoGEF619 都会以相似的程度激活 RhoGTPase。此外，我们发现 p63RhoGEF619 在 Gαq 偶联 GPCR 激活后重新定位到质膜，类似于众所周知的 Gα12/13 激活 RhoGEF 的激活机制。 p63RhoGEF619 向质膜的合成募集增加了 RhoGEF 对 RhoA 的活性，但完全激活需要通过 Gαq 进行变构激活。总之，这些发现揭示了 Gαq 在 RhoGEF 激活中的双重作用，因为它既招募又变构激活胞质 ARHGEF25 亚型。
Rho GTPases are master regulators of the eukaryotic cytoskeleton. The activation of Rho GTPases is governed by Rho guanine nucleotide exchange factors (GEFs). Three RhoGEF isoforms are produced by the gene ARHGEF25; p63RhoGEF580, GEFT and a recently discovered longer isoform of 619 amino acids (p63RhoGEF619). The subcellular distribution of p63RhoGEF580 and p63RhoGEF619 is strikingly different in unstimulated cells, p63RhoGEF580 is located at the plasma membrane and p63RhoGEF619 is confined to the cytoplasm. Interestingly, we find that both P63RhoGEF580 and p63RhoGEF619 activate RhoGTPases to a similar extent after stimulation of Gαq coupled GPCRs. Furthermore, we show that p63RhoGEF619 relocates to the plasma membrane upon activation of Gαq coupled GPCRs, resembling the well-known activation mechanism of RhoGEFs activated by Gα12/13. Synthetic recruitment of p63RhoGEF619 to the plasma membrane increases RhoGEF activity towards RhoA, but full activation requires allosteric activation via Gαq. Together, these findings reveal a dual role for Gαq in RhoGEF activation, as it both recruits and allosterically activates cytosolic ARHGEF25 isoforms.
登录
查看更多内容
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：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
影响因子：
4
作者：
Meyer, Bruno H.;Freuler, Felix;Siehler, Sandra
通讯作者：
Siehler, Sandra
影响因子：
56.9
作者：
Lutz, Susanne;Shankaranarayanan, Aruna;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
3.5
作者：
McPherson, CE;Eipper, BA;Mains, RE
通讯作者：
Mains, RE