While central dogma (DNA->RNA->protein) dominates our current view of biology, it is the energetics (the thermodynamics and kinetics) of the protein fold that translates information found in the genetic code into phenotype (DNA->RNA-> 'folding energetics'->protein function). While the energetics of the fold is clearly dictated by the chemical properties of the polypeptide chain (the amino acid sequence derived from an optimized genetic code), in biology it is the folding machinery, the ubiquitous chaperone systems [the chaperome (Cell (2006) 17:803)], that ultimately controls cellular protein homeostasis.
This is no more apparent then in the phenotypic transition from Archaea and Bacteria to the Eukaryota, a step reflecting the invention of subcellular compartmentalization- providing the basis for a marked expansion of biological protein folding capacity and function [(Cell (2005) 121: 73)]. Compartments of the exocytic and endocytic pathways provide specialized chemical and biological folding environments that generate the remarkable diversity of membrane architectures and functions observed in extant Eukaryota, and provide a means to coordinate the activities of the tightly integrated cellular communities comprising higher eukaryotes.
We will explore the opportunities afforded by protein folding energetics and variable chaperome environments to provide robust genetic and epigenetic mechanisms for eukaryote evolvability, and address the important implications of folding energetics on protein homeostasis in human disease.
