Journal
NATURE
Volume 528, Issue 7583, Pages 580-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature16162
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Funding
- National Science Foundation (NSF) [MCB-1445201, CHE-1332907]
- Defense Threat Reduction Agency (DTRA)
- Air Force Office of Scientific Research (AFOSR) [FA950-12-10112]
- Howard Hughes Medical Institute [HHMI-027779]
- Swiss National Science Foundation Postdoc Fellowship [PBZHP3-125470]
- Human Frontier Science Program Long-Term Fellowship [LT000070/2009-L]
- National Institutes of Health grant MINOS (Macromolecular Insights on Nucleic Acids Optimized by Scattering) [GM105404]
- United States Department of Energy program Integrated Diffraction Analysis Technologies (IDAT)
- Damon Runyon Cancer Research Foundation [DRG-2140-12]
- Merck fellowship of the Damon Runyon Cancer Research Foundation [DRG-2136-12]
- NIH [K99GM112982]
- Robert A. Welch Distinguished Chair in Chemistry
- Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]
- UC Office of the President, Multicampus Research Programs and Initiatives [MR-15-338599]
- Sandler Foundation
- National Institutes of Health
- National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- Swiss National Science Foundation (SNF) [PBZHP3-125470] Funding Source: Swiss National Science Foundation (SNF)
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1445201] Funding Source: National Science Foundation
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A central question in protein evolution is the extent to which naturally occurring proteins sample the space of folded structures accessible to the polypeptide chain. Repeat proteins composed of multiple tandem copies of a modular structure unit(1) are widespread in nature and have critical roles in molecular recognition, signalling, and other essential biological processes(2). Naturally occurring repeat proteins have been re-engineered for molecular recognition and modular scaffolding applications(3-5). Here we use computational protein design to investigate the space of folded structures that can be generated by tandem repeating a simple helix-loop-helix-loop structural motif. Eighty-three designs with sequences unrelated to known repeat proteins were experimentally characterized. Of these, 53 are monomeric and stable at 95 degrees C, and 43 have solution X-ray scattering spectra consistent with the design models. Crystal structures of 15 designs spanning a broad range of curvatures are in close agreement with the design models with root mean square deviations ranging from 0.7 to 2.5 angstrom. Our results show that existing repeat proteins occupy only a small fraction of the possible repeat protein sequence and structure space and that it is possible to design novel repeat proteins with precisely specified geometries, opening up a wide array of new possibilities for biomolecular engineering.
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