ArticleNature communications2018
HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease.
Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 44 citations in OpenAlex.
- Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).Cancer metastasis reviews · 2026Review
- Navigating Anemia Therapy in CKD With Hypoxia-Inducible Factor Activators: A Review.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2026Review
- Assessment of HIF2α mutational pathogenicity using microscale thermophoresis.Biology methods & protocols · 2026Review
- Article
- A structurally informed human protein-protein interactome reveals proteome-wide perturbations caused by disease mutations.Nature biotechnology · 2025Article
- Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes.Cancer discovery · 2025Article
- Head and neck paraganglioma in Pacak-Zhuang syndrome.JNCI cancer spectrum · 2025Article
- Time-resolved NMR detection of prolyl-hydroxylation in intrinsically disordered region of HIF-1α.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- [Advance in HIF expression and immune microenvironment in pseudohypoxic HNPGL].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2024Review
- Cathepsins L and B target HIF1α for oxygen-independent proteolytic cleavage.Scientific reports · 2024Article
- Deficiency in PHD2-mediated hydroxylation of HIF2α underlies Pacak-Zhuang syndrome.Communications biology · 2024Article
- Structurally-informed human interactome reveals proteome-wide perturbations by disease mutations.bioRxiv : the preprint server for biology · 2024Article
- Computational analysis of protein-protein interactions of cancer drivers in renal cell carcinoma.FEBS open bio · 2024Article
- Somatic EPAS1 Variants in Pheochromocytoma and Paraganglioma in Patients With Sickle Cell Disease.The Journal of clinical endocrinology and metabolism · 2023Article
- Article
- ComprehensiveHaematologica · 2023Article
- Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.Clinical endocrinology · 2022Review
- Article
- Erythrocytosis associated withHaematologica · 2022Article
- Erythrocytosis: genes and pathways involved in disease development.Blood transfusion = Trasfusione del sangue · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.