David Eisenberg focuses on protein interactions. In his experiments he studies the structural basis for conversion of normal proteins to the amyloid state and conversion of prions to the infectious state. In bioinformatic work, he derives information on protein interactions from genomic and proteomic data.
Amyloid and prion diseases are diseases of protein aggregation in which a normal, functional protein converts to an abnormal, aggregated protein. The systemic amyloid diseases, such as dialysis-related amyloidosis, are apparently caused by the accumulation of fibers until organs fail. The neurodegenerative amyloid diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and the prion conditions, seem to be caused by smaller oligomers, intermediate in size between monomers and fibers. Our goals are to understand the general features of the conversion to the amyloid state, why some of the diseases are transmissible between organisms and others not, what the structures of the toxic units are, and how they exert their toxic actions.
In 2005, we determined the first atomic-level structure for the spine of an amyloid fiber. This structure shows that the spine consists of two parallel beta sheets, packed across a tight, dry interface that we call a steric zipper. The structure of the spine explains the stability of amyloid, gives hints about the conversion process, and suggests why some proteins form amyloid while others do not. Since 2005, we have determined some 90 amyloid spines from 15 disease-related proteins, using a combination of bioinformatics and structural tools.
Amyloid fibers were long suspected to be the disease agents of Alzheimer's, Parkinson's, and the prion conditions, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Recently we identified a segment of the amyloid-forming protein alphaB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheetrich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-rayderived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers, and are currently being studied in our laboratory with biochemical, cellular, structural, and bioinformatics tools.
This work has also been supported by grants from the Department of Energy, the National Institutes of Health, and the National Science Foundation.