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The von Hippel-Lindau tumor suppressor (pVHL) targets hydroxylated alpha-subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated proteasomal destruction through direct interaction with the hydroxyproline binding pocket in its beta-domain. Although disruption of this process may contribute to VHL-associated tumor predisposition by up-regulation of HIF target genes, genetic and biochemical analyses support the existence of additional functions, including a role in the assembly of extracellular matrix. In an attempt to delineate these pathways, we searched for novel pVHL-binding proteins. Here we report a direct, hydroxylation-dependent interaction with alpha-chains of collagen IV. Interaction with pVHL was also observed with fibrillar collagen chains, but not the folded collagen triple helix. The interaction was suppressed by a wide range of tumor-associated mutations, including those that do not disturb the regulation of HIF, supporting a role in HIF-independent tumor suppressor functions.

Original publication




Journal article


J Biol Chem

Publication Date





13264 - 13269


Animals, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Line, Collagen Type IV, Extracellular Matrix, Humans, Hydroxylation, Hydroxyproline, Neoplasms, Proteasome Endopeptidase Complex, Protein Binding, Ubiquitin, Von Hippel-Lindau Tumor Suppressor Protein