Birth of the Metamorphome
Abstract
Christian Anfinsen was awarded a Nobel Prize in Chemistry in 1972 for his work on the apparent one-to-one relationship between the amino acyl sequence of a protein and its three-dimensional fold, which determines function (Anfinsen et al., 1961; Anfinsen and Haber, 1961). For decades, biochemistry courses throughout the world have been teaching the paradigm: Òone sequence, one foldÓ. The LiWang and Wang labs are challenging this paradigm by proposing that for numerous proteins one sequence determines more than one fold, and thus more than one function. These proteins are called "metamorphic", having the ability to jump reversibly between two distinctly different three-dimensional folds under native conditions. However, there are less than 10 proteins known to be metamorphic. X-ray diffraction crystallography, used for determining the vast majority of protein structures (104527 crystal structures = 90% of structures deposited in the Protein Data Bank), traps proteins in their lowest energy structure, and thus cannot detect whether a protein is metamorphic. The LiWang and Wang labs therefore believe that the number of metamorphic proteins in the Protein Data Bank (PDB) is much higher than just 10. (Not surprisingly, X-ray crystallography was not used in the serendipitous discoveries of the <10 known metamorphic proteins.) The objective of the LiWang and Wang labs is to uncover what they call the metamorphome, which is the population of metamorphic proteins in the PDB. It is anticipated that encoding multiple structures and functions in a single protein sequence will be found to be common. The project has two phases or aims: A) computational (identify candidate proteins that are potentially metamorphic), and B) experimental (test whether candidate proteins are actually metamorphic). Uncovering the metamorphome is expected have a transformative effect on long-held concepts of protein structure and function. It could also lead to engineering of metamorphic proteins, which are molecular switches, to act as sensors of small molecules or local environmental changes. It is expected that this project will 1) create a new field of research called the metamorphome, and 2) catalyze a major revision of long-held beliefs of protein structure and function, potentially overturning the Òone sequence, one foldÓ paradigm. The LiWang lab is qualified to carry out the experimental phase of the project, as evidenced by their discovery and characterization of the metamorphic properties of KaiB (Chang et al., 2012; Chang et al., 2011; Tseng et al., 2014), including one in the journal Science (Chang et al., 2015). For the computational phase of the project, the LiWang lab is collaborating with the lab of Professor Lee-Ping Wang at UC Davis. Dr. Wang is qualified for this aspect of the project, because he has extensive experience in computational modeling (http://www.lpwchem.org). Support from the ARO is justified for this research project, because it has the potential to overturn long-held paradigms, and give birth to new fields of research. It also has translational potential for novel applications. Thus, the LiWang and Wang labs believe that the vision of this proposal is well aligned with that of the ARO.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 07, 2018
- Source ID
- W911NF1710434
Entities
People
- Andy LiWang
Organizations
- Army Contracting Command
- United States Army
- University of California