Dataset Information

Raf-1 Cysteine-Rich Domain Increases the Affinity of K-Ras/Raf at the Membrane, Promoting MAPK Signaling.

ABSTRACT: K-Ras4B preferentially activates Raf-1. The high-affinity interaction of Ras-binding domain (RBD) of Raf with Ras was solved, but the relative position of Raf's cysteine-rich domain (CRD) in the Ras/Raf complex at the membrane and key question of exactly how it affects Raf signaling are daunting. We show that CRD stably binds anionic membranes inserting a positively charged loop into the amphipathic interface. Importantly, when in complex with Ras/RBD, covalently connected CRD presents the same membrane interaction mechanism, with CRD locating at the space between the RBD and membrane. To date, CRD's role was viewed in terms of stabilizing Raf-membrane interaction. Our observations argue for a key role in reducing Ras/RBD fluctuations at the membrane, thereby increasing Ras/RBD affinity. Even without K-Ras, via CRD, Raf-1 can recruit to the membrane; however, by reducing the Ras/RBD fluctuations and enhancing Ras/RBD affinity at the membrane, CRD promotes Raf's activation and MAPK signaling over other pathways.

SUBMITTER: Li S

PROVIDER: S-EPMC8183739 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Raf-1 Cysteine-Rich Domain Increases the Affinity of K-Ras/Raf at the Membrane, Promoting MAPK Signaling.

Li Shuai S Jang Hyunbum H Zhang Jian J Nussinov Ruth R

Structure (London, England : 1993) 20180208 3

K-Ras4B preferentially activates Raf-1. The high-affinity interaction of Ras-binding domain (RBD) of Raf with Ras was solved, but the relative position of Raf's cysteine-rich domain (CRD) in the Ras/Raf complex at the membrane and key question of exactly how it affects Raf signaling are daunting. We show that CRD stably binds anionic membranes inserting a positively charged loop into the amphipathic interface. Importantly, when in complex with Ras/RBD, covalently connected CRD presents the same ...[more]

PMID: 29429878

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most common clinical malignancies quite susceptible to recurrence and metastasis. Despite several improvements in therapeutic approaches, the prognosis remains poor due to the limited treatment options. A bioinformatics analysis based on TCGA databases revealed that the recombinant human L antigen family member 3 (LAGE3) might function as an effective prognostic and diagnostic biomarker for HCC, as LAGE3, a protein-coding gene, maintains several important biological functions and has a physiological significance in the CTAG family while simultaneously being involved in regulating the occurrence and invasion of numerous types of tumors. However, the LAGE3 gene's functional and regulatory mechanism in the progression of HCC remains unclear.MethodsThe LAGE3 level was investigated in 79 HCC tissues cases, ten HCC adjacent tissue cases, and six cases of normal liver tissues by IHC, while the LAGE3 level was evaluated in BEL-7404, SMCC-7721, Huh-7, HepG2, and MIHA cell lines by qRT-PCR and Western blot tests. Although the proliferation, migration, invasion, and apoptotic abilities of HCC cells were measured in vitro after silencing assay to probe the role of LAGE3 in HCC cells, the tumor xenograft growth experiment was used to verify the in vivo effect of LAGE3 gene knockdown on the growth of HCC tumors combined with bioinformatics analysis to study the LAGE3 mechanisms regulating HCC proliferation.ResultsOur results implied that LAGE3 was extensively expressed in HCC cell lines like BEL-7404, SMCC-7721, and Huh-7 cells as well as HCC tissues, but a lower expression was observed in HepG2 cells. Additionally, LAGE3 restrains cellular proliferation, promotes apoptotic pathways in HCC cells, and inhibits the growth of HCC tumors in vivo. Lastly, it was stated that LAGE3 might promote tumor development in HCC via PI3K/AKT/mTOR and Ras/RAF/MAPK pathways.ConclusionThis study shows that the development of specific LAGE3 target drugs might become new effective treatment modalities for HCC patients.

Dataset Information

Raf-1 Cysteine-Rich Domain Increases the Affinity of K-Ras/Raf at the Membrane, Promoting MAPK Signaling.

Publications

Raf-1 Cysteine-Rich Domain Increases the Affinity of K-Ras/Raf at the Membrane, Promoting MAPK Signaling.

Similar Datasets

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