Recent indings from the NIDDK Intramural Research Program are providing important insights about the formation of “β-barrels”—protein structures found in the exterior membranes of a large group of bacteria, many of which cause serious diseases. Most β-barrels act like pores, and many fulill essential roles like allowing nutrients to get into the space between outer and inner membranes that is characteristic of Gram-negative bacteria. Chloroplasts—the structures
inside plant cells where light is converted into chemical energy—and mitochondria—the structures in cells of both plants and animals that extract energy from a variety of fuel sources—share this double-membrane organization with Gram-negative bacteria, from which they are thought to have evolved, and also have β-barrel pores in the exterior membrane. The initial steps in the synthesis of proteins that contain β-barrels are the same as those of other proteins. The final step—insertion of the barrel portion into the outer membrane—is known to be accomplished by a group of other proteins called the “barrel-assembly machinery (BAM)” complex.
To obtain clues about how the BAM complex fulills this role, the NIDDK scientists studied a critical component of this complex, the BamA protein, itself a β-barrel protein. They determined the three-dimensional structures of BamA from two different disease-causing bacteria and compared them to known structures of other β-barrel proteins. This approach helped them to identify unique features of BamA, and to provide likely explanations for their role in assembly of β-barrels.
The findings suggest that parts of BamA that are on the interior side of the membrane are able to bind to proteins requiring membrane insertion, to open a passage into BamA’s β-barrel, and—working with another part of BamA that can move up and down in the barrel—in effect, to act like a ratchet to thread a portion of the new protein into the pore. The BamA pore itself has a feature that thins the bacterial membrane at a key point, and opens a issure along the side of the BamA barrel, facilitating movement out of the pore and into the adjacent membrane. The researchers hypothesize that this process repeats until all parts of the new protein needed to form a β-barrel have been properly arranged in the membrane, and the two proteins separate.
The researchers also found that a simpler mechanism may be available for a subset of β-barrel proteins, where the inner, grappling/ratcheting portions of BamA might insert the new protein directly into the part of the membrane that is thinned by BamA, without actually passing through the interior of BamA’s barrel. Further research will be needed to determine if these fascinating processes operate for β-barrel proteins in the outer membranes of other bacteria, or of mitochondria and chloroplasts.
Noinaj N, Kuszak AJ, Gumbart JC, et al. Structural insight
into the biogenesis of β-barrel membrane proteins. Nature
501: 385-390, 2013.