The genotype-phenotype landscape of an allosteric protein

Tack, Drew S.; Tonner, Peter D.; Pressman, Abe; Olson, Nathan D.; Levy, Sasha F.; Romantseva, Eugenia F.; Alperovich, Nina; Vasilyeva, Olga; Ross, David

doi:10.15252/msb.202010179

Title: The genotype-phenotype landscape of an allosteric protein

Abstract

Allostery is a fundamental biophysical mechanism that underlies cellular sensing, signaling, and metabolism. Yet a quantitative understanding of allosteric genotype-phenotype relationships remains elusive. Here, we report the large-scale measurement of the genotype-phenotype landscape for an allosteric protein: the lac repressor from Escherichia coli, LacI. Using a method that combines long-read and short-read DNA sequencing, we quantitatively measure the dose-response curves for nearly 10⁵ variants of the LacI genetic sensor. The resulting data provide a quantitative map of the effect of amino acid substitutions on LacI allostery and reveal systematic sequence-structure-function relationships. We find that in many cases, allosteric phenotypes can be quantitatively predicted with additive or neural-network models, but unpredictable changes also occur. For example, we were surprised to discover a new band-stop phenotype that challenges conventional models of allostery and that emerges from combinations of nearly silent amino acid substitutions.

Authors:

^[1];

^[1]; Pressman, Abe ^[1];

^[1];

^[2];

^[1]; Alperovich, Nina ^[1]; Vasilyeva, Olga ^[1];

^[1]

National Inst. of Standards and Technology (NIST), Gaithersburg, MD (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States); Joint Initiative for Metrology in Biology, Stanford, CA (United States)

Publication Date:: Mon Mar 01 00:00:00 EST 2021

Research Org.:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 1781600

Grant/Contract Number:: AC02-76SF00515

Resource Type:: Accepted Manuscript

Journal Name:: Molecular Systems Biology

Additional Journal Information:: Journal Volume: 17; Journal Issue: 3; Journal ID: ISSN 1744-4292

Publisher:: Wiley

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; allostery; genetic sensor; genotype-phenotype relationships; highthroughput measurements; transcription factor

Citation Formats


                    Tack, Drew S., Tonner, Peter D., Pressman, Abe, Olson, Nathan D., Levy, Sasha F., Romantseva, Eugenia F., Alperovich, Nina, Vasilyeva, Olga, and Ross, David. The genotype-phenotype landscape of an allosteric protein.  United States: N. p., 2021. 
Web.  doi:10.15252/msb.202010179.

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                    Tack, Drew S., Tonner, Peter D., Pressman, Abe, Olson, Nathan D., Levy, Sasha F., Romantseva, Eugenia F., Alperovich, Nina, Vasilyeva, Olga, & Ross, David. The genotype-phenotype landscape of an allosteric protein.  United States.  https://doi.org/10.15252/msb.202010179

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                    Tack, Drew S., Tonner, Peter D., Pressman, Abe, Olson, Nathan D., Levy, Sasha F., Romantseva, Eugenia F., Alperovich, Nina, Vasilyeva, Olga, and Ross, David. Mon .  
"The genotype-phenotype landscape of an allosteric protein".  United States.  https://doi.org/10.15252/msb.202010179.  https://www.osti.gov/servlets/purl/1781600.

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@article{osti_1781600,

  title        = {The genotype-phenotype landscape of an allosteric protein},

  author       = {Tack, Drew S. and Tonner, Peter D. and Pressman, Abe and Olson, Nathan D. and Levy, Sasha F. and Romantseva, Eugenia F. and Alperovich, Nina and Vasilyeva, Olga and Ross, David},

  abstractNote = {Allostery is a fundamental biophysical mechanism that underlies cellular sensing, signaling, and metabolism. Yet a quantitative understanding of allosteric genotype-phenotype relationships remains elusive. Here, we report the large-scale measurement of the genotype-phenotype landscape for an allosteric protein: the lac repressor from Escherichia coli, LacI. Using a method that combines long-read and short-read DNA sequencing, we quantitatively measure the dose-response curves for nearly 105 variants of the LacI genetic sensor. The resulting data provide a quantitative map of the effect of amino acid substitutions on LacI allostery and reveal systematic sequence-structure-function relationships. We find that in many cases, allosteric phenotypes can be quantitatively predicted with additive or neural-network models, but unpredictable changes also occur. For example, we were surprised to discover a new band-stop phenotype that challenges conventional models of allostery and that emerges from combinations of nearly silent amino acid substitutions.},

  doi          = {10.15252/msb.202010179},

  journal      = {Molecular Systems Biology},

  number       = 3,

  volume       = 17,

  place        = {United States},

  year         = {Mon Mar 01 00:00:00 EST 2021},

  month        = {Mon Mar 01 00:00:00 EST 2021}

}

Copy to clipboard

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Similar Records

Title: The genotype-phenotype landscape of an allosteric protein

Abstract

Citation Formats

Allostery and Intrinsic Disorder Mediate Transcription Regulation by Conditional Cooperativity journal, July 2010

Network of epistatic interactions within a yeast snoRNA journal, April 2016

Allosteric transition pathways in the lactose repressor protein core domains: Asymmetric motions in a homodimer journal, November 2003

Quantifying side-chain conformational variations in protein structure journal, November 2016

The fitness landscape of a tRNA gene journal, April 2016

Genetic Studies of the lac Repressor. XIV. Analysis of 4000 Altered Escherichia coli lac Repressors Reveals Essential and Non-essential Residues, as well as "Spacers" which do not Require a Specific Sequence journal, July 1994

A scalable double-barcode sequencing platform for characterization of dynamic protein-protein interactions journal, May 2017

Positions 94−98 of the Lactose Repressor N-Subdomain Monomer−Monomer Interface Are Critical for Allosteric Communication journal, October 2010

Formation of the hinge helix in the lac represser is induced upon binding to the lac operator journal, November 1996

Allostery: an illustrated definition for the ‘second secret of life’ journal, September 2008

Protein activity regulation by conformational entropy journal, July 2012

The coming of age of de novo protein design journal, September 2016

Optimized PCR conditions minimizing the formation of chimeric DNA molecules from MPRA plasmid libraries journal, July 2019

Tradeoffs and Optimality in the Evolution of Gene Regulation journal, August 2011

Engineering alternate cooperative-communications in the lactose repressor protein scaffold journal, April 2013

Sparse estimation of mutual information landscapes quantifies information transmission through cellular biochemical reaction networks journal, April 2020

Functional plasticity and evolutionary adaptation of allosteric regulation journal, September 2020

Lac repressor genetic map in real space journal, September 1997

Positional preference of proline in α-helices journal, January 1999

Purification of the Escherichia coli purine regulon repressor and identification of corepressors. journal, January 1990

Multi-environment fitness landscapes of a tRNA gene journal, April 2018

Bartender: a fast and accurate clustering algorithm to count barcode reads journal, October 2017

Estimation in Parallel Randomized Experiments journal, January 1981

Decomposing Complex Cooperative Ligand Binding into Simple Components: Connections between Microscopic and Macroscopic Models journal, July 2004

Long Short-Term Memory journal, November 1997

Engineering an allosteric transcription factor to respond to new ligands journal, December 2015

Thermodynamic Analysis of Mutant lac Repressors journal, May 2011

Amino acid preferences for specific locations at the ends of alpha helices journal, June 1988

Protein volume in solution journal, January 1972

Statistical Mechanics of Monod–Wyman–Changeux (MWC) Models journal, May 2013

Perturbation from a Distance: Mutations that Alter LacI Function through Long-Range Effects † journal, December 2003

Reducing chimera formation during PCR amplification to ensure accurate genotyping journal, December 2010

Structure of a variant of lac repressor with increased thermostability and decreased affinity for operator 1 1Edited by D. Rees journal, October 2001

Dynamically driven protein allostery journal, August 2006

Plasticity of quaternary structure: Twenty-two ways to form a LacI dimer journal, February 2001

Local fitness landscape of the green fluorescent protein journal, May 2016

Toward a prospective molecular evolution journal, May 2016

A simple method for displaying the hydropathic character of a protein journal, May 1982

Mutational inversion of control of the lactose operon of Escherichia coli journal, May 1971

Predictive shifts in free energy couple mutations to their phenotypic consequences journal, August 2019

Interpretations arising from Wrightian and Malthusian fitness under strong frequency dependent selection journal, April 2013

Pairwise and higher-order genetic interactions during the evolution of a tRNA journal, May 2018

Measurements of translation initiation from all 64 codons in E. coli journal, February 2017

Stan : A Probabilistic Programming Language journal, January 2017

Dimerization-based control of cooperativity journal, January 2014

Tuning Transcriptional Regulation through Signaling: A Predictive Theory of Allosteric Induction journal, April 2018

Gaussian Processes for Machine Learning book, January 2005

On the nature of allosteric transitions: A plausible model journal, May 1965

Crystal Structure of the Lactose Operon Repressor and Its Complexes with DNA and Inducer journal, March 1996

The ensemble nature of allostery journal, April 2014

Influence of the second amino acid on recombinant protein expression journal, December 2010

Engineering allostery journal, December 2014

Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome journal, August 2019

Counting absolute numbers of molecules using unique molecular identifiers journal, November 2011

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA journal, March 2019

Allostery and Intrinsic Disorder Mediate Transcription Regulation by Conditional Cooperativity
journal, July 2010

Network of epistatic interactions within a yeast snoRNA
journal, April 2016

Allosteric transition pathways in the lactose repressor protein core domains: Asymmetric motions in a homodimer
journal, November 2003

Quantifying side-chain conformational variations in protein structure
journal, November 2016

The fitness landscape of a tRNA gene
journal, April 2016

Genetic Studies of the lac Repressor. XIV. Analysis of 4000 Altered Escherichia coli lac Repressors Reveals Essential and Non-essential Residues, as well as "Spacers" which do not Require a Specific Sequence
journal, July 1994

A scalable double-barcode sequencing platform for characterization of dynamic protein-protein interactions
journal, May 2017

Positions 94−98 of the Lactose Repressor N-Subdomain Monomer−Monomer Interface Are Critical for Allosteric Communication
journal, October 2010

Formation of the hinge helix in the lac represser is induced upon binding to the lac operator
journal, November 1996

Allostery: an illustrated definition for the ‘second secret of life’
journal, September 2008

Protein activity regulation by conformational entropy
journal, July 2012

The coming of age of de novo protein design
journal, September 2016

Optimized PCR conditions minimizing the formation of chimeric DNA molecules from MPRA plasmid libraries
journal, July 2019

Tradeoffs and Optimality in the Evolution of Gene Regulation
journal, August 2011

Engineering alternate cooperative-communications in the lactose repressor protein scaffold
journal, April 2013

Sparse estimation of mutual information landscapes quantifies information transmission through cellular biochemical reaction networks
journal, April 2020

Functional plasticity and evolutionary adaptation of allosteric regulation
journal, September 2020

Lac repressor genetic map in real space
journal, September 1997

Positional preference of proline in α-helices
journal, January 1999

Purification of the Escherichia coli purine regulon repressor and identification of corepressors.
journal, January 1990

Multi-environment fitness landscapes of a tRNA gene
journal, April 2018

Bartender: a fast and accurate clustering algorithm to count barcode reads
journal, October 2017

Estimation in Parallel Randomized Experiments
journal, January 1981

Decomposing Complex Cooperative Ligand Binding into Simple Components: Connections between Microscopic and Macroscopic Models
journal, July 2004

Long Short-Term Memory
journal, November 1997

Engineering an allosteric transcription factor to respond to new ligands
journal, December 2015

Thermodynamic Analysis of Mutant lac Repressors
journal, May 2011

Amino acid preferences for specific locations at the ends of alpha helices
journal, June 1988

Protein volume in solution
journal, January 1972

Statistical Mechanics of Monod–Wyman–Changeux (MWC) Models
journal, May 2013

Perturbation from a Distance: Mutations that Alter LacI Function through Long-Range Effects ^†
journal, December 2003

Reducing chimera formation during PCR amplification to ensure accurate genotyping
journal, December 2010

Structure of a variant of lac repressor with increased thermostability and decreased affinity for operator 1 1Edited by D. Rees
journal, October 2001

Dynamically driven protein allostery
journal, August 2006

Plasticity of quaternary structure: Twenty-two ways to form a LacI dimer
journal, February 2001

Local fitness landscape of the green fluorescent protein
journal, May 2016

Toward a prospective molecular evolution
journal, May 2016

A simple method for displaying the hydropathic character of a protein
journal, May 1982

Mutational inversion of control of the lactose operon of Escherichia coli
journal, May 1971

Predictive shifts in free energy couple mutations to their phenotypic consequences
journal, August 2019

Interpretations arising from Wrightian and Malthusian fitness under strong frequency dependent selection
journal, April 2013

Pairwise and higher-order genetic interactions during the evolution of a tRNA
journal, May 2018

Measurements of translation initiation from all 64 codons in E. coli
journal, February 2017

Stan : A Probabilistic Programming Language
journal, January 2017

Dimerization-based control of cooperativity
journal, January 2014

Tuning Transcriptional Regulation through Signaling: A Predictive Theory of Allosteric Induction
journal, April 2018

Gaussian Processes for Machine Learning
book, January 2005

On the nature of allosteric transitions: A plausible model
journal, May 1965

Crystal Structure of the Lactose Operon Repressor and Its Complexes with DNA and Inducer
journal, March 1996

The ensemble nature of allostery
journal, April 2014

Influence of the second amino acid on recombinant protein expression
journal, December 2010

Engineering allostery
journal, December 2014

Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome
journal, August 2019

Counting absolute numbers of molecules using unique molecular identifiers
journal, November 2011

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA
journal, March 2019