In This Issue

1335 G-protein-coupled receptor structures were not built in a day

Tracy M. Blois and James U. Bowie

One of the most visible recent achievements of structural biology is solution of a number of G-protein-coupled receptor structures, which are part of an ongoing revolution in membrane protein determination. Blois and Bowie review some of the new and emerging technologies that are helping to fuel the field's transformation. The review incorporates the new interactive graphics features now available in Protein Science.

1388 Cofactor binding and enzymatic activity in an unevolved superfamily of de novo designed 4-helix bundle proteins

Shona C. Patel, Luke H. Bradley, Sayuri P. Jinadasa, and Michael H. Hecht

To examine the functional potential of an unevolved superfamily of de novo proteins, Patel, et al. characterize a binary patterned library and demonstrate that a substantial fraction of novel of 4-helix bundles can bind heme and catalyze reactions. This work describes the first demonstration that a designed library of de novo sequences readily yields proteins possessing a range of functions. The results also demonstrate that sequences that have not been selected by evolution – either in nature or in the laboratory – can nonetheless perform biological activities and serve as a “feedstock” for molecular evolution. In the realm of synthetic biology, this work is a step towards the production of biological activities encoded by macromolecules that were not derived from natural organisms, but instead were synthesized de novo in the laboratory.

1486 A chimeric mechanism for polyvalent trans-phosphorylation of PKA by PDK1

Robert A. Romano, Natarajan Kannan, Alexandr P. Kornev, Craig J. Allison, and Susan S. Taylor

The AGC subfamily of protein kinases are typically activated by phosphorylation of their activation loops by another kinase, PDK1. A conserved C-terminal tail, essential for AGC kinase activity, is absent in PDK1. Using peptide arrays, Romano, et al. describe a novel motif in the C-tail of PKA that interacts with PDK1 and is conserved in Akt and PRK2, showing how PDK1 can function without a tail and still recognize its substrates. Modeling studies using PKA show how PDK1 can recruit an extended C-tail from its substrate kinase to create an active kinase. This study demonstrates how two kinases evolved as symbiotic partners.

1521 Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process

Jed J. W. Wiltzius, Stuart A. Sievers, Michael R. Sawaya, and David Eisenberg

The pancreatic hormone Islet Amyloid Polypeptide (IAPP or amylin) is often deposited in fibril form in patients suffering from diabetes type 2. In this report, Wiltzius et al. offer structural and biochemical evidence that IAPP may pass through a helical intermediate on the way to its fibril form. This work also offers a structural basis for the finding that insulin opposes fibrillation of IAPP, perhaps by binding to the helical intermediate.