Min Jung-Hyun, Yang Haifeng, Ivan Mircea, Gertler Frank, Kaelin William G, Pavletich Nikola P
Cellular Biochemistry and Biophysics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Science. 2002 Jun 7;296(5574):1886-9. doi: 10.1126/science.1073440. Epub 2002 May 9.
The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.
冯·希佩尔-林道肿瘤抑制因子（pVHL）对缺氧诱导因子（HIF）进行泛素化修饰，在细胞对氧可用性变化的反应中起核心作用。只有当HIF中一个保守的脯氨酸被羟基化时，pVHL才会与HIF结合，这种修饰是依赖氧的。一个包含20个残基的HIF-1α肽-pVHL-ElonginB-ElonginC复合物的1.85埃结构表明，HIF-1α以延伸的β链样构象与pVHL结合。羟脯氨酸插入到pVHL疏水核心的一个间隙中，该位点是致瘤突变的热点，其4-羟基被埋在内部的丝氨酸和组氨酸残基识别。虽然β片层样相互作用有助于复合物的稳定性，但羟脯氨酸接触对于信号传导的严格特异性至关重要。
