| Autor: |
Mishal Tariq, Teppei Ikeya, Naoyuki Togashi, Louise Fairall, Carlos Bueno-Alejo, Syun Kamei, Beatriz Romartinez-Alonso, Miguel Angel Muro Campillo, Andrew J. Hudson, Yutaka Ito, John W.R. Schwabe, Cyril Dominguez, Kayoko Tanaka |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.10.10.511529 |
| Popis: |
About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human K-Ras4B and the Ras association (RA) domain of Rgl2 (Rgl2RA), one of the RA-containing RalGEFs. We show that the G12V oncogenic K-Ras4B mutation increases the affinity with Rgl2RA. The crystal structure of the K-Ras4BG12V: Rgl2RAcomplex shows a 2:2 heterotetramer where the Switch I and Switch II regions of each K-RasG12Vinteract with both Rgl2RAmolecules. This structural arrangement is highly similar to the H-RasE31K:RALGDSRAcrystal structure and is distinct from the well-characterised Ras:Raf complex. Importantly, the G12V mutation was found at the dimer interface of K-Ras4BG12Vwith its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs, and offers a possible mechanistic explanation for how the oncogenic K-Ras4BG12Vhyperactivates the RalA/B pathway.Summary BlurbThe work reports that the K-RAS4B.G12V oncogenic mutation increases the affinity with Rgl2, an activator of RalA/B and provides a structural explanation by analysing the K-Ras4B(G12V):Rgl2 complex crystal structure where the G12V mutation resides at the interface of the complex. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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