16 November 2007
Michael J Behe
This is the fifth of five posts in which I reply to Dr. Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.
Finally, Dr. Musgrave objects to my placing viral protein – cellular protein interactions in a separate category from cellular protein-cellular protein interactions. In Chapter 8 of The Edge of Evolution I had written:
Another, more important point to note is that I’m considering just cellular proteins binding to other cellular proteins, not to foreign proteins. Foreign proteins injected into a cell by an invading virus or bacterium make up a different category. The foreign proteins of pathogens almost always are intended to cripple a cell in any way possible. Since there are so many more ways to break a machine than to improve it, this is the kind of task at which Darwinism excels. Like throwing a wad of chewing gum into a finely tuned machine, it’s relatively easy to clog a system — much easier than making the system in the first place. Destructive protein-protein binding is much easier to achieve by chance. (pp. 148-149)
This is simply not true, either generally or in the particular case of Vpu. Importantly, your statement shows that you do not understand what Vpu does. Vpu down regulates the surface protein CD4 (the Viroporin activity is something separate related to viral release). It does not “gum-up” CD4, it specifically binds to it….
Dr. Musgrave misunderstands my point. I did not say that Vpu acted as a nonspecific wad of chewing gum. Rather, my point is a general one, that, initially, when during the course of evolution a viral or bacterial protein is injected for the first time into a cell, it is encountering a new environment, one it hasn’t adapted to before, and which hasn’t adapted to it. In that case there are many “targets of opportunity” for the foreign protein. If by serendipity it sticks to some cellular protein to a certain degree, and that association interferes to a degree with the function of the cellular protein, then that will likely benefit the virus, and the association can be strengthened by mutations to the viral protein over time. After a while the association can become very specific, as Vpu’s has.
On the other hand, consider cellular proteins. Cellular proteins must continually exist in a confined space, dense with many other cellular proteins, and so they are normally selected to not bind to most other cellular proteins. In other words, for eons the surfaces of cellular proteins have been honed so as to not interact with almost any other protein in a very concentrated cellular milieu. (Work has shown protein surfaces also adapt to particular sub-cellular compartments.) (6) As the textbook Biochemistryby Voet and Voet puts it: (7)
Proteins, because of their multiple polar and nonpolar groups, stick to almost anything; anything, that is, but other proteins. This is because the forces of evolution have arranged the surface groups of proteins so as to prevent their association under physiological conditions. If this were not the case, their resulting nonspecific aggregation would render proteins functionally useless.
How does this affect the situation when, in some future environment, it might be beneficial for two cellular proteins that had worked separately, to associate, to develop a new protein-protein binding site? From considerations of shape space (8), it seems in general it would be very difficult. Work on antibodies and other proteins shows that a protein which is “tolerant” of a second protein (that is, does not bind it) will be tolerant of mutants of that protein, until a relatively large number of amino acids have changed. (9,10) It seems likely that this will be the case for cellular proteins too. (11) If so, that means that two proteins which had previously tolerated each other over eons in a cell would have to undergo multiple mutations to acquire the ability to specifically bind to each other.
That’s why I put cellular protein-protein interactions in a different category from foreign protein-cellular protein interactions.
1. Gomez,L.M., Pacyniak,E., Flick,M., Hout,D.R., Gomez,M.L., Nerrienet,E., Ayouba,A., Santiago,M.L., Hahn,B.H., and Stephens,E.B. 2005. Vpu-mediated CD4 down-regulation and degradation is conserved among highly divergent SIV(cpz) strains.Virology 335:46-60.
2. Hout,D.R., Mulcahy,E.R., Pacyniak,E., Gomez,L.M., Gomez,M.L., and Stephens,E.B. 2004. Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1. Curr. HIV. Res. 2:255-270.
3. Butler,I.F., Pandrea,I., Marx,P.A., and Apetrei,C. 2007. HIV genetic diversity: biological and public health consequences.Curr. HIV. Res. 5:23-45.
4. Gonzalez,M.E. and Carrasco,L. 2003. Viroporins. FEBS Lett. 552:28-34.
5. Mehnert T, et al., Biophysical characterization of Vpu from HIV-1 suggests a channel-pore dualism. Proteins. 2007 Oct 1; doi: 10.1002/prot.21642.
6. Andrade,M.A., O’Donoghue,S.I., and Rost,B. 1998. Adaptation of protein surfaces to subcellular location. J. Mol. Biol.276:517-525.
7. Voet,D. and Voet,J.G. 2004. Biochemistry, 3rd ed. J. Wiley & Sons: New York, p. 265.
8. Smith,D.J., Forrest,S., Hightower,R.R., and Perelson,A.S. 1997. Deriving shape space parameters from immunological data. J. Theor. Biol. 189:141-150.
9. Champion,A.B., Soderberg,K.L., and Wilson,A.C. 1975. Immunological comparison of azurins of known amino acid sequence. Dependence of cross-reactivity upon sequence resemblance. J. Mol. Evol. 5:291-305.
10. Nossal,G.J. 1993. Tolerance and ways to break it. Ann. N. Y. Acad. Sci. 690:34-41.
11. Guo,Z.Y., Shen,L., Gu,W., Wu,A.Z., Ma,J.G., and Feng,Y.M. 2002. In vitro evolution of amphioxus insulin-like peptide to mammalian insulin. Biochemistry41:10603-10607.