Home Blog of Signal Transduction Cytoskeletal Signaling HSP (HSP90) Effects of cancer-associated point mutations on the structure, function, and stability of succinate dehydrogenase A

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Effects of cancer-associated point mutations on the structure, function, and stability of succinate dehydrogenase A

After the discovery of mutations in the gene encoding the Krebs cycle enzyme succinate dehydrogenase A (SDHA) in paragangliomas and other tumors, genetic SDHA variants have been reported to be important biomarkers. However, the molecular mechanisms in SDHA mutation-induced carcinogenesis remain unclear. Using overlapping PCR, protein expression and purification, immunoblotting and -precipitation, enzyme activity measurements, protein aggregation and degradation assays, and a homology model, here we demonstrate that the properties of cancer-associated SDHA variants arising from point mutations are closely related to their structure and stability. Furthermore, SDHA mutations resulted in a temperature/urea concentration-dependent increase in aggregation of the purified SDHA protein. Compared with wild-type SDHA, the degradation of the SDHA variants was increased in 293T cells after 17-(allylamino)geldanamycin (17-AAG)-induced inhibition of heat shock protein 90 (HSP90). The homology model further revealed that changes in conformational and SDHA protein stability appear to be associated with these point mutations. Taken together, our findings provide information important for understanding the molecular mechanisms of SDHA mutations in tumors.

Related Products

Cat.No. Product Name Information
S1141 Tanespimycin (17-AAG) Tanespimycin (17-AAG, CP127374, NSC-330507, KOS 953) is a potent HSP90 inhibitor with IC50 of 5 nM in a cell-free assay, having a 100-fold higher binding affinity for HSP90 derived from tumour cells than HSP90 from normal cells. Tanespimycin (17-AAG) induces apoptosis, necrosis, autophagy and mitophagy. Phase 3.

Related Targets

HSP (HSP90)