6BVB

Crystal structure of HIF-2alpha-pVHL-elongin B-elongin C

Summary for 6BVB

• Entry DOI: 10.2210/pdb6bvb/pdb
• Descriptor: von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (5 entities in total)
• Functional Keywords: e3 ubiquitin ligase, gene regulation
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 44890.91

Authors

Tarade, D.,Ohh, M.,Lee, J.E. (deposition date: 2017-12-12, release date: 2018-08-01, Last modification date: 2023-10-04)

Primary citation

Tarade, D.,Robinson, C.M.,Lee, J.E.,Ohh, M.
HIF-2 alpha-pVHL complex reveals broad genotype-phenotype correlations in HIF-2 alpha-driven disease.
Nat Commun, 9:3359-3359, 2018

PubMed Abstract: It is definitively established that mutations in transcription factor HIF-2α are causative of both neuroendocrine tumors (class 1 disease) and polycythemia (class 2 disease). However, the molecular mechanism that underlies this emergent genotype-phenotype relationship has remained unclear. Here, we report the structure of HIF-2α peptide bound to pVHL-elongin B-elongin C (VBC) heterotrimeric complex, which shows topographical demarcation of class 1 and 2 mutations affecting residues predicted, and demonstrated via biophysical analyses, to differentially impact HIF-2α-pVHL interaction interface stability. Concordantly, biochemical experiments showed that class 1 mutations disrupt pVHL affinity to HIF-2α more adversely than class 2 mutations directly or indirectly via impeding PHD2-mediated hydroxylation. These findings suggest that neuroendocrine tumor pathogenesis requires a higher HIF-2α dose than polycythemia, which requires only a mild increase in HIF-2α activity. These biophysical data reveal a structural basis that underlies, and can be used to predict de novo, broad genotype-phenotype correlations in HIF-2α-driven disease.

PubMed: 30135421
DOI: 10.1038/s41467-018-05554-1

Experimental method

X-RAY DIFFRACTION (2.002 Å)