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Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasisResearch in context
- Source :
- EBioMedicine, Vol 45, Iss, Pp 108-123 (2019), EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- Background: Hydrogen Sulfide (H2S), a third member of gasotransmitter family along with nitric oxide (NO) and carbon monoxide (CO), exerts a wide range of cellular and molecular actions in our body. There is a large body of evidence suggesting that H2S plays an important role in cancer metastasis; however, the molecular mechanisms of H2S-mediated acceleration of cancer metastasis remain unknown. Methods: We examined the promote effects of H2S on phenotype of gastric cancer (GC) cells (including those of express wild type CD36 and mutant CD36) in vitro and in vivo. GC patients' samples were used for clinical translational significance evaluation. Findings: H2S triggered lipid metabolism reprogramming by significantly up-regulating the expression of the fatty-acid receptor CD36 (CD36) and directly activating CD36 in GC cells. Mechanistically, a disulfide bond located between cysteine (Cys)333 and Cys272 within the CD36 protein structure that was labile to H2S-mediated modification. The long chain-fatty acid (LC-FA) binding pocket was capped by a turn in the CD36 protein, located between helical and sheet structures that were stabilized by the Cys333-Cys272. This limited the secondary binding between LC-FAs and lysine (Lys)334. Breaking the Cys333-Cys272 disulfide bond restored the second LC-FA binding conformation of CD36. Targeting CD36 in vivo blocked H2S-promoted metastasis and improved animal survival. Interpretation: These findings identify that the Cys333-Cys272 disulfide bond disrupted the integrity of the second LC-FA binding conformation of CD36. Therefore, CD36 can directly activate LC-FA access to the cytoplasm by acting as a direct target molecule for H2S. Keywords: H2S, CD36, Disulfide bond, Long chain-fatty acid, Nrf2, Metastasis
- Subjects :
- 0301 basic medicine
CD36 Antigens
Research paper
CD36
Mutant
Lysine
lcsh:Medicine
Receptors, Odorant
Metastasis
Mice
0302 clinical medicine
Protein structure
Cell Movement
Long chain-fatty acid
Disulfides
Hydrogen Sulfide
Neoplasm Metastasis
Receptor
lcsh:R5-920
biology
Chemistry
H2S
Fatty Acids
General Medicine
Cell biology
030220 oncology & carcinogenesis
Heterografts
lcsh:Medicine (General)
Nitric Oxide
General Biochemistry, Genetics and Molecular Biology
Nrf2
Arthropod Proteins
03 medical and health sciences
Protein Domains
Stomach Neoplasms
Cell Line, Tumor
medicine
Animals
Humans
Neoplasm Invasiveness
Cysteine
Cell Proliferation
Disulfide bond
lcsh:R
Wild type
medicine.disease
equipment and supplies
030104 developmental biology
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....650cb5da17c5f337cf46b83fc250d285