title: Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor.
abstract: 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.
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grosfeld
authors.forename: Ineke P
authors.initials: IP
authors.lastname: Stolze
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Cockman
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Mariola
authors.initials: M
authors.lastname: Edelmann
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Norma
authors.initials: N
authors.lastname: Masson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D006909:Hydroxyproline / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024141:Collagen Type IV; D006909:Hydroxyproline; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein