PDBsum entry 1vcb

Transcription

PDB id: 1vcb

Contents

Protein chains

98 a.a. *

88 a.a. *

142 a.a. *

Waters ×454

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structure of the vhl-Elonginc-Elonginb complex: implications for vhl tumor suppressor function.

Authors

C.E.Stebbins, W.G.Kaelin, N.P.Pavletich.

Ref.

Science, 1999, 284, 455-461. [DOI no: 10.1126/science.284.5413.455]

PubMed id

10205047

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.

Figure 2.
Fig. 2. Structural elements and conservation of VHL, ElonginC, and ElonginB. (A) Sequence of VHL demonstrating that tumor-derived missense mutations are divided between the and domains of VHL, whereas residues contacting ElonginC cluster in the domain (40). The histogram represents 279 missense mutations in the database (29). The six most frequently mutated amino acids are labeled. Shaded squares above each residue describe the relative solvent exposure of a residue in a hypothetical VHL monomer. Blue boxes indicate residues that make hydrogen bonds or van der Waals contacts with ElonginC. (B) Sequence identity between human ElonginC and ElonginC homologs is indicated by yellow, and identity between human ElonginC and human Skp1, aligned with the program THREADER2, is indicated by green. Residues that make hydrogen bonds or van der Waals contacts with VHL are indicated by red and those contacting ElonginB by blue. Secondary structure and solvent accessibility are as in (A). A disordered segment in ElonginC is indicated with a dashed line and extended insertions in the alignments are indicated by lines below the sequence alignments. (C) Sequence identity between human ElonginB and ElonginB homologs is indicated by yellow. Identity between human ElonginB and human ubiquitin, which maps primarily to hydrophobic core residues, is indicated by green. Residues that make hydrogen bonds or van der Waals contacts with ElonginC are indicated by blue. Secondary structure and solvent accessibility are as in (A), and disordered segments in the ElonginB structure are indicated with a dashed line. (D) Close-up view of the - interface of VHL. VHL amino acids are in yellow and those of ElonginC are in cyan. White dashed lines indicate hydrogen bonds, red atoms indicate oxygen and blue, nitrogen. A red circle with the letter "M" indicates a residue that is one of the six most frequently mutated in tumors.

Figure 3.
Fig. 3. ElonginC binds VHL and ElonginB across two separate interfaces. (A) The VHL-ElonginC interface consists of an intermolecular hydrophobic four-helix cluster augmented by additional contacts. VHL and ElonginC secondary structural elements are shown in red and blue, respectively. VHL amino acids are in yellow and those of ElonginC are in cyan. Hydrogen bonds are indicated by white dashed lines. Red atoms indicate oxygen and blue, nitrogen. A red circle with the letter "M" indicates a residue that is one of the six most frequently mutated in cancer. The ElonginC pocket where the VHL Leu^158 binds is made up of Tyr^76, Phe^93, Leu^103, and Ala^107, and Cys^112 (40). (B) The parallel strand- strand interaction around which the ElonginC-ElonginB interface centers is indicated by a two-headed arrow (four hydrogen bonds). ElonginB and ElonginC secondary structural elements are shown in green and blue, respectively. ElonginB amino acids are in magenta and those of ElonginC are in cyan.

The above figures are reprinted by permission from the AAAs: Science (1999, 284, 455-461) copyright 1999.