Mitochondrial β-Barrel Proteins, an Exclusive Club?

This paper is a correspondence responding to the discovery of the "β-signal" by Kutik et al.¹. the β-signal is a signal for the integration of mitochondrial β-barrel outer membrane proteins (MBOMPs) into the membrane. The β-signal is a C-terminal motif, spanning 8 residues with a consensus sequence of P_o.G..H_y.H_y, where {P_o = polar, G = Glycine, H_y = large hydrophobic}. Kutik et al., experimentally demonstrated the role of the β-signal in 3 out of the 5 known families of MBOMPs viz. Tom40, Porin, Mdm10; and corroborated their results with multiple alignment, which suggested a role for the β-signal in a fourth MBOMP, Sam50.

We performed an informatics analysis of the Eukaryotic proteome (as found in UniProt), considering evolutionary conserved occurrences of C-terminal substrings matching the β-signal as well as subcellular localization annotation and predicted secondary structure.

The bacteria proteome contains 100's of families of β-barrel outer membrane proteins. From this fact, and preliminary informatics analysis, it was once thought that the yeast proteome would also contain 100's of MBOMPs². To our surprise, our search did not yield many candidate new mitochondrial MBOMPs, but rather provided circumstantial evidence that there may not be many more families of MBOMPs left to be discovered. We were able to suggest that the remaining known family of MBOMP's (Mmm2) may have a functioning β-signal; removed from the C-terminus but at the C-terminal end of a region of predicted β secondary structure. We also found that a reported mitochondrial outer membrane protein, Uth1, contains a potential β-signal near its C-terminus and might possibly represent the sixth MBOMP family. Finally, we noted that the residue after G in the β-signal is almost always hydrophobic (but usually small -- see Kutik et al.'s response to our correspondence). Combining our comments with theirs, the new consensus sequence is P_o.Gh_y.H_y.H_y, where {H_y = large hydrophobic, h_y = hydrophobic}. Note that the occurrence of hydrophobic residues at every other position is consistent with the membrane environment β secondary structure shown for the β-signal in recent structural studies, e.g. Hiller et al.³

References

1. "Dissecting membrane insertion of mitochondrial β-barrel proteins.",
S Kutik, D Stojanovski, L Becker, T Becker, M Meinecke, V üger, C Prinz, C Meisinger, B Guiard, R Wagner, N Pfanner & N Wiedemann,
Cell, 132:1011-24, 2008.

2. "The versatile β-barrel membrane protein",
William C Wimley,
Curr. Opin. Struct. Biol., 13:404-11, 2003.

3. "Solution structure of the integral human membrane protein VDAC-1 in detergent micelles",
S. Hiller, R. G. Garces, T. J. Malia, V. Y. Orekhov, M. Colombini & G. Wagner,
Science, 321:1206-10, 2008.