scholarly journals Evolution of fold switching in a metamorphic protein

Science ◽  
2020 ◽  
Vol 371 (6524) ◽  
pp. 86-90
Author(s):  
Acacia F. Dishman ◽  
Robert C. Tyler ◽  
Jamie C. Fox ◽  
Andrew B. Kleist ◽  
Kenneth E. Prehoda ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Protein Design ◽  
Structural Constraints ◽  
Ancestral Reconstruction ◽  
Dimer Interface ◽  
Multiple Structures ◽  
Metamorphic Protein ◽  
Equal Population ◽  
Chemokine Family ◽  
Protein Design And Engineering

Metamorphic proteins switch between different folds, defying the protein folding paradigm. It is unclear how fold switching arises during evolution. With ancestral reconstruction and nuclear magnetic resonance, we studied the evolution of the metamorphic human protein XCL1, which has two distinct folds with different functions, making it an unusual member of the chemokine family, whose members generally adopt one conserved fold. XCL1 evolved from an ancestor with the chemokine fold. Evolution of a dimer interface, changes in structural constraints and molecular strain, and alteration of intramolecular protein contacts drove the evolution of metamorphosis. Then, XCL1 likely evolved to preferentially populate the noncanonical fold before reaching its modern-day near-equal population of folds. These discoveries illuminate how one sequence has evolved to encode multiple structures, revealing principles for protein design and engineering.

scholarly journals Amino-acid site variability among natural and designed proteins

2013 ◽  
Author(s):  
Eleisha L. Jackson ◽  
Noah Ollikainen ◽  
Arthur W. Covert III ◽  
Tanja Kortemme ◽  
Claus O. Wilke
Keyword(s):  
Amino Acid ◽  
Protein Design ◽  
Protein Sequences ◽  
Structural Constraints ◽  
Scoring Functions ◽  
Solvent Exposure ◽  
Backbone Flexibility ◽  
Hydrophobic Residues ◽  
Designed Proteins ◽  
Site Variability

Computational protein design attempts to create protein sequences that fold stably into pre-specified structures. Here we compare alignments of designed proteins to alignments of natural proteins and assess how closely designed sequences recapitulate patterns of sequence variation found in natural protein sequences. We design proteins using RosettaDesign, and we evaluate both fixed-backbone designs and variable-backbone designs with different amounts of backbone flexibility. We find that proteins designed with a fixed backbone tend to underestimate the amount of site variability observed in natural proteins while proteins designed with an intermediate amount of backbone flexibility result in more realistic site variability. Further, the correlation between solvent exposure and site variability in designed proteins is lower than that in natural proteins. This finding suggests that site variability is too uniform across different solvent exposure states (i.e., buried residues are too variable or exposed residues too conserved). When comparing the amino acid frequencies in the designed proteins with those in natural proteins we find that in the designed proteins hydrophobic residues are underrepresented in the core. From these results we conclude that intermediate backbone flexibility during design results in more accurate protein design and that either scoring functions or backbone sampling methods require further improvement to accurately replicate structural constraints on site variability.

scholarly journals Amino-acid site variability among natural and designed proteins

2013 ◽  
Author(s):  
Eleisha L. Jackson ◽  
Noah Ollikainen ◽  
Arthur W. Covert III ◽  
Tanja Kortemme ◽  
Claus O. Wilke
Keyword(s):  
Amino Acid ◽  
Protein Design ◽  
Protein Sequences ◽  
Structural Constraints ◽  
Scoring Functions ◽  
Solvent Exposure ◽  
Backbone Flexibility ◽  
Hydrophobic Residues ◽  
Designed Proteins ◽  
Site Variability

Computational protein design attempts to create protein sequences that fold stably into pre-specified structures. Here we compare alignments of designed proteins to alignments of natural proteins and assess how closely designed sequences recapitulate patterns of sequence variation found in natural protein sequences. We design proteins using RosettaDesign, and we evaluate both fixed-backbone designs and variable-backbone designs with different amounts of backbone flexibility. We find that proteins designed with a fixed backbone tend to underestimate the amount of site variability observed in natural proteins while proteins designed with an intermediate amount of backbone flexibility result in more realistic site variability. Further, the correlation between solvent exposure and site variability in designed proteins is lower than that in natural proteins. This finding suggests that site variability is too uniform across different solvent exposure states (i.e., buried residues are too variable or exposed residues too conserved). When comparing the amino acid frequencies in the designed proteins with those in natural proteins we find that in the designed proteins hydrophobic residues are underrepresented in the core. From these results we conclude that intermediate backbone flexibility during design results in more accurate protein design and that either scoring functions or backbone sampling methods require further improvement to accurately replicate structural constraints on site variability.

scholarly journals ProtaBank: A repository for protein design and engineering data

2019 ◽  
Vol 28 (3) ◽  
pp. 672-672
Author(s):  
Connie Y. Wang ◽  
Paul M. Chang ◽  
Marie L. Ary ◽  
Benjamin D. Allen ◽  
Roberto A. Chica ◽  
...  
Keyword(s):  
Protein Design ◽  
Engineering Data ◽  
Protein Design And Engineering

Fluorinated amino acids in protein design and engineering

2002 ◽  
Vol 31 (6) ◽  
pp. 335-341 ◽  
Author(s):  
Nicholas C. Yoder ◽  
Krishna Kumar
Keyword(s):  
Amino Acids ◽  
Protein Design ◽  
Fluorinated Amino Acids ◽  
Protein Design And Engineering

scholarly journals Structures of the transcriptional regulator BgaR, a lactose sensor

2019 ◽  
Vol 75 (7) ◽  
pp. 639-646 ◽  
Author(s):  
Janet Newman ◽  
Karine Caron ◽  
Tom Nebl ◽  
Thomas S. Peat
Keyword(s):  
Binding Affinity ◽  
Transcriptional Regulator ◽  
Dimer Interface ◽  
Space Groups ◽  
Saccharide Binding ◽  
Multiple Structures ◽  
Sad Phasing ◽  
Nonspecific Interactions ◽  
Jelly Roll ◽  
Micromolar Range

The structure of BgaR, a transcriptional regulator of the lactose operon inClostridium perfringens, has been solved by SAD phasing using a mercury derivative. BgaR is an exquisite sensor of lactose, with a binding affinity in the low-micromolar range. This sensor and regulator has been captured bound to lactose and to lactulose as well as in a nominal apo form, and was compared with AraC, another saccharide-binding transcriptional regulator. It is shown that the saccharides bind in the N-terminal region of a jelly-roll fold, but that part of the saccharide is exposed to bulk solvent. This differs from the classical AraC saccharide-binding site, which is mostly sequestered from the bulk solvent. The structures of BgaR bound to lactose and to lactulose highlight how specific and nonspecific interactions lead to a higher binding affinity of BgaR for lactose compared with lactulose. Moreover, solving multiple structures of BgaR in different space groups, both bound to saccharides and unbound, verified that the dimer interface along a C-terminal helix is similar to the dimer interface observed in AraC.

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