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. 2002 Mar 19;99(6):3428-33.
doi: 10.1073/pnas.062525799.

Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus

Qiulong Huang  1 , Andrew M Petros, Herbert W Virgin, Stephen W Fesik, Edward T Olejniczak
Affiliations

Solution structure of a Bcl-2 homolog from Kaposi sarcoma virus

Qiulong Huang et al. Proc Natl Acad Sci U S A. .

Abstract

Kaposi sarcoma-associated herpes virus (KSHV) contains a gene that has functional and sequence homology to the apoptotic Bcl-2 family of proteins [Sarid, R., Sato, T., Bohenzky, R. A., Russo, J. J. & Chang, Y. (1997) Nat. Med. 3, 293-298]. The viral Bcl-2 protein promotes survival of infected cells and may contribute to the development of Kaposi sarcoma tumors [Boshoff, C. & Chang, Y. (2001) Annu. Rev. Med. 52, 453-470]. Here we describe the solution structure of the viral Bcl-2 homolog from KSHV. Comparison of the KSHV Bcl-2 structure to that of Bcl-2 and Bcl-x(L) shows that although the overall fold is the same, there are key differences in the lengths of the helices and loops. Binding studies on peptides derived from the Bcl-2 homology region 3 of proapoptotic family members indicate that the specificity of the viral protein is very different from what was previously observed for Bcl-x(L) and Bcl-2, suggesting that the viral protein has evolved to have a different mechanism of action than the host proteins.

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Figures

Figure 1
Figure 1
Sequence alignment based on the observed secondary structure of KSHV Bcl-2 and human full-length Bcl-xL and Bcl-2. α-Helices for KSHV Bcl-2 are shown above the sequence. The BH regions are shown below the sequence. The transmembrane domain (TM) is indicated below the sequence.
Figure 2
Figure 2
(A) Backbone (N,Cα,C′) superposition of 10 low-energy NMR-derived structures for viral KSHV Bcl-2. Helices are numbered with respect to those observed in the structure of Bcl-xL. (B) Ribbon (36) depiction of the average-minimized structure for viral KSHV Bcl-2. The central helix, α5, is colored yellow. (C) Solvent-accessible surface showing hydrophobic groove for viral KSHV Bcl-2. Leucine, isoleucine, valine, methionine, tyrosine, phenylalanine, and tryptophan residues are colored yellow. Aspartate and glutamate are colored red. Lysine, arginine, and histidine are colored blue. All other residue types are colored gray.
Figure 3
Figure 3
Comparison of KSHV Bcl-2 (A) to Bcl-xL (B) and to Bcl-2 (C). Residues of the hydrophobic groove that are homologous to those that contact the Bak and Bad peptides when complexed to Bcl-xL are shown along with the tryptophan residue of the NWGR sequence. To emphasize the differences in the structured regions of the proteins, we have made our comparisons to truncated forms of Bcl-2 and Bcl-xL (17, 18).
Figure 4
Figure 4
Solvent-accessible surface showing the hydrophobic groove of KSHV Bcl-2. The orientation of A is the same as in Fig. 2C whereas B is the opposite face. Residues that shift significantly when the BH3 peptide of Bak is titrated into a solution of the protein are colored magenta.
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