Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / GARCIA-SAEZ Isabel

Survivin and HBXIP

Survivin has been revealed as a bifunctional protein. It not only plays an essential role in the chromosome passenger complex (CPC) but it is also involved in an anti-apoptotic activity together with its activator partner HBXIP (Hepatitis B X-Interacting Protein). Moreover, Survivin has become a potential therapeutical target because its overexpression has been detected in several cancer types.

Survivin has been one of the main subjects of the laboratory for years. It is here where it has been demonstrated that this small protein of 17 kDa is involved in the passenger complex (1). The laboratory also participated in the obtention of the first structural determination of the protein (2) (figure 1).

Figure 1: survivin dimer

In our team we pursue this multidisciplinary approach that goes from cell biology to the structure. More particularly we have been working in the crystallogenesis of isoforms of Survivin and associated proteins. In that context we have obtained the three-dimensional structure of the cofactor of Survivin that stimulates its anti-apoptotic activity, the protein HBXIP.

Structural determination of HBXIP

Hepatitis B X-interacting protein (HBXIP) is a ubiquitous protein that acts as anti-apoptotic cofactor with Survivin. Together they promote suppression of the activation of pro-caspase-9 that is the protease located at the top of the mitochondrial cascade that promotes cell death. Initially, HBXIP was described as the cellular partner of the Hepatitis B virus HBx protein. HBx is an oncogenic protein involved in apoptosis regulation among many other processes.

We have obtained the crystal structure of the shortest isoform of HBXIP (91 aa long, 11 kDa) at 1.5Å resolution (3). HBXIP crystal shows a monomer per asymmetric unit. However SAXS studies (in collaboration with Dr. Frank Gabel, IBS) for the sample used for crystallization indicates that the protein is predominantly in dimeric form in solution (figure 2).

Figure 2: Experimental SAXS curve and back-calculated curves for HBXIP monomer and dimer.

The monomer of HBXIP shows a profilin/like fold, common to a superfamily of proteins, the Roadblock/LC7 domain family, that are dimers involved in protein-protein interactions. This dimer can be found in the crystal when symmetric molecules are generated around the asymmetric unit (figure 3 and 4).

Figure 3: HBXIP dimer in the crystal

The dimer shows an extended β-sheet area formed by 10 anti-parallel β-strands from both subunits. Another interesting aspect of the proposed HBXIP dimer interface is the presence of a small leucine zipper between the two α2 helices of each monomer.

Figure 4: HBXIP dimer

The HBXIP crystal structure represents a step in the understanding of the cellular role of HBXIP since the HBXIP folding (extended β-sheet surface) may serve as scaffold for the recruitment of various proteins involved in key processes such as apoptosis, centrosome maturation and mitochondria function.


1. Skoufias DA, Mollinari C, Lacroix FB, Margolis RL. Human survivin is a kinetochore-associated passenger protein. J. Cell Biol. 2000, 151(7): 1575-82

2. Chantalat L, Skoufias DA, Kleman JP, Jung B, Dideberg O, Margolis RL. Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Mol Cell. 2000, 6(1) : 183-9

3. Garcia-Saez, I. , Lacroix, F.B., Blot, D., Gabel, F. & Skoufias, D.A. Structural Characterization of HBXIP: The Protein That Interacts with the Anti-Apoptotic Protein Survivin and the Oncogenic Viral Protein HBx. J Mol Biol. 2010, 405(2): 331-340