Studying protein complexes with structural genomics

Proteins in vivo often function in complexes, and indeed, that?s how many individual structural biology efforts approach them. Not structural genomics efforts, though: For all their high-throughput methods, structural genomics pipelines typically treat proteins individually, in isolation. A linkurl:paper;http://www.pnas.org/cgi/content/abstract/0602606103v1 released May 11 in __PNAS__ could help bridge this gap. The new method, developed by linkurl:David Eisenberg;http://www.doe-mbi.ucla.edu/People/Eisenberg/ of the University of California, Los Angeles, and colleagues combines a series of linkurl:bioinformatics analyses;http://mysql5.mbi.ucla.edu/cgi-bin/functionator/pronav that scour a genome for clues suggesting that two genes are functionally linked (that is, that they both participate in a particular complex, pathway, or biological function), with experimental methods to validate those predictions. The group focused on two large, but poorly characterized protein families in the __Mycobacterium tuberculosis__ genome, called PE and PPE. Of 17 PE and 11 PPE proteins tested in their study, only one was soluble in __E. coli__ on its own, and that one was unfolded. But when they jointly expressed one member of each family on a polycistronic message in bacteria, the proteins formed a highly expressed, heterodimeric complex. The resulting crystal structure reveals why neither protein was soluble individually: both proteins expose an "extended apolar interface" that is only buried (and thus, stabilized) when the two proteins form a complex. This is precisely the reason why approaching proteins piecemeal is so hit or miss: many proteins simply don?t behave well in isolation. That observation dovetails nicely with a lesson I learned a few months ago at linkurl:Keystone;http://www.the-scientist.com/blog/display/23090/ -- that structural genomics approaches, especially of eukaryotic proteins, have high failure rates. Given the experience of Eisenberg et al. with the PE and PPE families, I wonder if perhaps this new approach might not go a long way toward improving the odds.

Studying protein complexes with structural genomics

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