Nature Structural Biology pp 381 - 388

It's generally believed that a protein's amino acid sequence determines its three-dimensional structure and folding pathway. This view has led scientists to search for residues that are directly involved in forming the native structure of a protein. A report in the May issue of Nature Structural Biology now suggests a new role for proline in directing the folding of transmembrane proteins: it may prevent the formation of misfolded structures.

One of the many mutations that cause cystic fibrosis replaces a specific proline in the disease-associated protein called CFTR. These CFTR mutants fail to fold into the functional structure and often form aggregates inside the cell. To define how this proline directs the folding of CFTR, Phil Thomas and colleagues (University of Texas Southwestern Medical Center, USA) characterize the behavior of model peptides that correspond to the region within CFTR containing the crucial proline site. They show that a peptide carrying the wild type proline residue forms a native-like helical structure and successfully inserts into the membrane, but mutant peptides form non-native structures and insert into the membrane with much lower efficiency. These and other observations suggest that the proline residue at this position promotes correct folding of CFTR by disfavoring misfolded conformations.

Nature Structural Biology pp 326 - 331 and pp 332 - 336

Researchers in the UK and Japan have identified core protein structural elements that may be important in amyloid fibril formation. These findings, reported in the May issue of Nature Structural Biology, now provide a structural framework for understanding the fibril formation process, and may ultimately aid in designing treatments for amyloid diseases, including Alzheimer�s disease, CJD, and dialysis-related amyloidosis.

The fibrils of � ₂-microglobulin (� ₂m) are associated with amyloidosis in patients undergoing hemodialysis. To understand how functional protein molecules turn into fibrils, Sheena Radford and coworkers (University of Leeds) determined the most stable regions of the amyloid-forming intermediate of � ₂m. The regions roughly correspond to the core �-sheets in the functional � ₂m and have features remarkably similar to those seen in another amyloid disease-associated protein, transthyretin.

In an independent study, Yuji Goto and colleagues (Osaka University) and collaborators (the National Institute of Advanced Industrial Science and Technology, and Fukui University) examine the structure present at the other extreme of the fibril formation process � that is, in the assembled �₂m amyloid fibrils. Their results suggested that the functional protein structure is partially reconfigured during formation of the amyloid cross-�-sheet structure. Notably, the core structure in the fibril is very similar to that in the amyloid-forming intermediate. These results suggest that partially ordered �-sheets may play an important role in the formation of the cross-�-sheet structures that ultimately assemble into amyloid fibrils.