The Structure of Amyloid and Prions
Amyloid and prion diseases are diseases of protein conformation in which a normal, functional protein converts to an abnormal, aggregated, fibrillar state. Amyloid and prion fibrils are often associated with fatal diseases and are always characterized by a signature x-ray diffraction pattern, the "cross-β" pattern. Our goal is to understand the general features of the conversion, including what accounts for the transmissibility of these diseases and why there is a barrier between species, which sometimes can be penetrated. In 2005, we determined the first atomic-level structure for the cross-β spine of amyloid. This structure shows that the spine consists of two parallel β sheets, packed across a tight, dry interface that we call a steric zipper. The structure of the spine explains the stability of the amyloid, gives hints about the conversion process and species barrier, and also suggests why some proteins may form amyloid while others do not. Since 2005, we have determined some 60 cross-β spines from 10 disease-related proteins, using a combination of bioinformatics and structural tools.

Protein Interactions
The lives of cells are controlled by the networks of their macromolecular interactions. These interactions are the basis of the many metabolic and signaling pathways of the cell, and the molecular machines that carry out the work of the cell. We have inferred many of these pathways and complexes from analysis of fully sequenced genomes, using methods such as phylogenetic profiles, Rosetta Stone, and gene neighbor. A Prolinks database has been created for making this information generally available, and the inferred functional linkages in 600 genomes are available on the Web at http://mysql5.mbi.ucla.edu/cgi-bin/functionator/pronav. We have also devised methods for visualization and interpretation of the functional linkages, such as the clustered genome-wide functional linkage map. In recent work, we have extended the method of phylogenetic profiles from the study of pairs of proteins to the study of triplets, offering deeper insights into metabolic pathways.

	Structures of RNase A... Hinge loops of the RNase A major dimer...

We have gathered experimental reports of protein interactions in the Database of Interacting Proteins http://dip.doe-mbi.ucla.edu/. This open resource offers information on some 60,000 reports of protein interactions.