Structure of the VHL-ElonginC-ElonginB Complex: Implications for VHL Tumor Suppressor Function

Abstract

Mutation of the VHL tumor suppressor is associated with the inherited von Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible proteins. The structure of the ternary complex at 2.7 angstrom resolution shows two interfaces, one between VHL and ElonginC and another between ElonginC and ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL responsible for ElonginC binding. A mutational patch on a separate domain of VHL indicates a second macromolecular binding site. The structure extends the similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins for degradation, supporting the hypothesis that VHL may function in an analogous pathway.

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

“…Modeling of C. elegans ELC‐1 and human TCEB1, a homolog of elongin C, was performed by using SWISS‐MODEL (http://swissmodel.expasy.org/) (Biasini et al ., 2014), based on the crystal structures of mammalian VHL–elongin C–elongin B complex and SOCS3–elongin B–elongin C complex (Stebbins et al ., 1999; Babon et al ., 2008). Structures were revisualized and aligned using PyMOL (http://www.pymol.org/) (Schrodinger, 2010).…”

Ubiquitination-mediated protein degradation and modification: an emerging theme in plant-microbe interactions

“…Structural analysis indicated that Cullin1 (most of the time abbreviated as CUL1) acts as a scaffold that directs other members of the SCF complex to bring the ubiquitin-loaded E2s and the substrate in proximity to promote the transferring of ubiquitin directly from the E2 to the substrates [26]. Besides Cullin1, recent data indicated that Cullin2 and Cullin3 also form similar groups of E3 ligases, in which an elongin C-SOCS module or a BTB protein replaces the SKP1-F-box protein module npg in the Cullin1-type SCF E3 ligase, respectively [27][28][29]. In the Arabidopsis genome, around 700 genes are predicted to encode proteins containing the 40 amino-acid F-box motif [30].…”

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

“…The candidate 178-amino acid d-VHL protein can be aligned along its entire length with the smaller of the two h-VHLs ( Figure 1a; Gnarra et al, 1994;Beroud et al, 1998;Stebbins et al, 1999). d-VHL has an overall 22% identity to h-VHL and is 50% similar when conserved amino acid changes were considered ( Figure 1b).…”

“…One outstanding distinction between the two proteins, however, is that d-VHL lacks the N-terminal extension found in the larger form of the h-VHL. h-VHL gene encodes two biologically active proteins as a result of in-frame alternative AUG codon usage (Gnarra et al, 1994;Beroud et al, 1998;Stebbins et al, 1999). However, no functional signi®cance has been assigned to the extra 53 amino acids at the N-terminus of the large h-VHL.…”