Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor.
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.
Grosfeld
Alexandra
A
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
Stolze
Ineke P
IP
Cockman
Matthew E
ME
Pugh
Christopher W
CW
Edelmann
Mariola
M
Kessler
Benedikt
B
Bullock
Alex N
AN
Ratcliffe
Peter J
PJ
Masson
Norma
N
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*
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