Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

Hao, Yue; Pierce, Elizabeth; Roe, Daniel; Morita, Maho; McIntosh, John A.; Agarwal, Vinayak; Cheatham, III, Thomas E.; Schmidt, Eric W.; Nair, Satish K.

doi:10.1073/pnas.1609869113

Title: Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

Abstract

The cyanobactin prenyltransferases catalyze a series of known or unprecedented reactions on millions of different substrates, with no easily observable recognition motif and exquisite regioselectivity. Here we define the basis of broad substrate tolerance for the otherwise uncharacterized TruF family. We determined the structures of the Tyr-prenylating enzyme PagF, in complex with an isoprenoid donor analog and a panel of linear and macrocyclic peptide substrates. Unexpectedly, the structures reveal a truncated barrel fold, wherein binding of large peptide substrates is necessary to complete a solvent-exposed hydrophobic pocket to form the catalytically competent active site. Kinetic, mutational, chemical, and computational analyses revealed the structural basis of selectivity, showing a small motif within peptide substrates that is sufficient for recognition by the enzyme. Attaching this 2-residue motif to two random peptides results in their isoprenylation by PagF, demonstrating utility as a general biocatalytic platform for modifications on any peptide substrate.

Authors:

Hao, Yue ^[1]; Pierce, Elizabeth ^[2]; Roe, Daniel ^[2]; Morita, Maho ^[2]; McIntosh, John A. ^[2]; Agarwal, Vinayak ^[1]; Cheatham, III, Thomas E. ^[2]; Schmidt, Eric W. ^[2]; Nair, Satish K. ^[1]

Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States)
Univ. of Utah, Salt Lake City, UT (United States)

Publication Date:: Mon Nov 21 00:00:00 EST 2016

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:: National Institutes of Health (NIH)

OSTI Identifier:: 1335987

Grant/Contract Number:: GM102602; GM103219

Resource Type:: Accepted Manuscript

Journal Name:: Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:: Journal Volume: 113; Journal Issue: 49; Journal ID: ISSN 0027-8424

Publisher:: National Academy of Sciences

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; RiPP; biosynthesis; prenylation; crystallography

Citation Formats


                    Hao, Yue, Pierce, Elizabeth, Roe, Daniel, Morita, Maho, McIntosh, John A., Agarwal, Vinayak, Cheatham, III, Thomas E., Schmidt, Eric W., and Nair, Satish K. Molecular basis for the broad substrate selectivity of a peptide prenyltransferase.  United States: N. p., 2016. 
Web.  doi:10.1073/pnas.1609869113.

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                    Hao, Yue, Pierce, Elizabeth, Roe, Daniel, Morita, Maho, McIntosh, John A., Agarwal, Vinayak, Cheatham, III, Thomas E., Schmidt, Eric W., & Nair, Satish K. Molecular basis for the broad substrate selectivity of a peptide prenyltransferase.  United States.  https://doi.org/10.1073/pnas.1609869113

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                    Hao, Yue, Pierce, Elizabeth, Roe, Daniel, Morita, Maho, McIntosh, John A., Agarwal, Vinayak, Cheatham, III, Thomas E., Schmidt, Eric W., and Nair, Satish K. Mon .  
"Molecular basis for the broad substrate selectivity of a peptide prenyltransferase".  United States.  https://doi.org/10.1073/pnas.1609869113.  https://www.osti.gov/servlets/purl/1335987.

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@article{osti_1335987,

  title        = {Molecular basis for the broad substrate selectivity of a peptide prenyltransferase},

  author       = {Hao, Yue and Pierce, Elizabeth and Roe, Daniel and Morita, Maho and McIntosh, John A. and Agarwal, Vinayak and Cheatham, III, Thomas E. and Schmidt, Eric W. and Nair, Satish K.},

  abstractNote = {The cyanobactin prenyltransferases catalyze a series of known or unprecedented reactions on millions of different substrates, with no easily observable recognition motif and exquisite regioselectivity. Here we define the basis of broad substrate tolerance for the otherwise uncharacterized TruF family. We determined the structures of the Tyr-prenylating enzyme PagF, in complex with an isoprenoid donor analog and a panel of linear and macrocyclic peptide substrates. Unexpectedly, the structures reveal a truncated barrel fold, wherein binding of large peptide substrates is necessary to complete a solvent-exposed hydrophobic pocket to form the catalytically competent active site. Kinetic, mutational, chemical, and computational analyses revealed the structural basis of selectivity, showing a small motif within peptide substrates that is sufficient for recognition by the enzyme. Attaching this 2-residue motif to two random peptides results in their isoprenylation by PagF, demonstrating utility as a general biocatalytic platform for modifications on any peptide substrate.},

  doi          = {10.1073/pnas.1609869113},

  journal      = {Proceedings of the National Academy of Sciences of the United States of America},

  number       = 49,

  volume       = 113,

  place        = {United States},

  year         = {Mon Nov 21 00:00:00 EST 2016},

  month        = {Mon Nov 21 00:00:00 EST 2016}

}

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Works referencing / citing this record:

Molecular Insight into the Mg ²⁺ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1
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Title: Molecular basis for the broad substrate selectivity of a peptide prenyltransferase

Abstract

Citation Formats

The chemical toolbox for monitoring protein fatty acylation and prenylation journal, June 2010

Natural combinatorial peptide libraries in cyanobacterial symbionts of marine ascidians journal, November 2006

Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products journal, June 2005

Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A web tool for generating protein sequence similarity networks journal, August 2015

Assessing the Combinatorial Potential of the RiPP Cyanobactin tru Pathway journal, July 2014

Protein Prenylation: Molecular Mechanisms and Functional Consequences journal, June 1996

Catalytic Mechanism of Aromatic Prenylation by NphB journal, March 2012

Metabolic model for diversity-generating biosynthesis journal, February 2016

Structure of PatF from Prochloron didemni journal, May 2013

Circular Logic: Nonribosomal Peptide-like Macrocyclization with a Ribosomal Peptide Catalyst journal, November 2010

Identification of Significant Residues in the Substrate Binding Site of Bacillus stearothermophilus Farnesyl Diphosphate Synthase † journal, January 1996

Enzymatic Basis of Ribosomal Peptide Prenylation in Cyanobacteria journal, August 2011

Cyanobactins—ribosomal cyclic peptides produced by cyanobacteria journal, February 2010

The ABBA family of aromatic prenyltransferases: broadening natural product diversity journal, February 2008

Catalytic Mechanism of Stereospecific Formation of cis-Configured Prenylated Pyrroloindoline Diketopiperazines by Indole Prenyltransferases journal, December 2013

Post-Translational Isoprenylation of Tryptophan journal, August 2011

Chapter 23 Cyanobactin Ribosomally Synthesized Peptides—A Case of Deep Metagenome Mining book, January 2009

Prenyl transfer to aromatic substrates: genetics and enzymology journal, April 2009

Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks journal, November 2003

Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiont of Lissoclinum patella journal, May 2005

Highly Diverse Cyanobactins in Strains of the Genus Anabaena journal, December 2009

Protein Prenylation: Enzymes, Therapeutics, and Biotechnology Applications journal, November 2014

Crystal Structure of Recombinant Farnesyl Diphosphate Synthase at 2.6-.ANG. Resolution journal, September 1994

The structural biology of patellamide biosynthesis journal, December 2014

Linking Chemistry and Genetics in the Growing Cyanobactin Natural Products Family journal, April 2011

Mutagenesis Studies of Protein Farnesyltransferase Implicate Aspartate β352 as a Magnesium Ligand journal, October 2003

Regulation of peptide antibiotic production in Bacillus journal, March 1993

Genome Mining Expands the Chemical Diversity of the Cyanobactin Family to Include Highly Modified Linear Peptides journal, August 2013

Mechanistic studies on the indole prenyltransferases journal, January 2015

Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions journal, December 2012

Multifunctional Prenylated Peptides for Live Cell Analysis journal, June 2009

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria journal, August 2009

Structure and Mechanism of the Magnesium-Independent Aromatic Prenyltransferase CloQ from the Clorobiocin Biosynthetic Pathway journal, December 2010

Using Marine Natural Products to Discover a Protease that Catalyzes Peptide Macrocyclization of Diverse Substrates journal, February 2009

A global assembly line for cyanobactins journal, April 2008

Acein-1, a novel angiotensin-I-converting enzyme inhibitory peptide isolated from tryptic hydrolysate of human plasma journal, November 1998

Follow the leader: the use of leader peptides to guide natural product biosynthesis journal, December 2009

Recognition Sequences and Substrate Evolution in Cyanobactin Biosynthesis journal, March 2014

Converting Peptides into Drug Leads by Lipidation journal, March 2012

Molecular Insight into the Mg 2+ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1 journal, May 2018

Molecular Insight into the Mg 2+ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1 journal, May 2018

Parallel lives of symbionts and hosts: chemical mutualism in marine animals journal, January 2018

The chemical toolbox for monitoring protein fatty acylation and prenylation
journal, June 2010

Natural combinatorial peptide libraries in cyanobacterial symbionts of marine ascidians
journal, November 2006

Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products
journal, June 2005

Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A web tool for generating protein sequence similarity networks
journal, August 2015

Assessing the Combinatorial Potential of the RiPP Cyanobactin tru Pathway
journal, July 2014

Protein Prenylation: Molecular Mechanisms and Functional Consequences
journal, June 1996

Catalytic Mechanism of Aromatic Prenylation by NphB
journal, March 2012

Metabolic model for diversity-generating biosynthesis
journal, February 2016

Structure of PatF from Prochloron didemni
journal, May 2013

Circular Logic: Nonribosomal Peptide-like Macrocyclization with a Ribosomal Peptide Catalyst
journal, November 2010

Identification of Significant Residues in the Substrate Binding Site of Bacillus stearothermophilus Farnesyl Diphosphate Synthase ^†
journal, January 1996

Enzymatic Basis of Ribosomal Peptide Prenylation in Cyanobacteria
journal, August 2011

Cyanobactins—ribosomal cyclic peptides produced by cyanobacteria
journal, February 2010

The ABBA family of aromatic prenyltransferases: broadening natural product diversity
journal, February 2008

Catalytic Mechanism of Stereospecific Formation of cis-Configured Prenylated Pyrroloindoline Diketopiperazines by Indole Prenyltransferases
journal, December 2013

Post-Translational Isoprenylation of Tryptophan
journal, August 2011

Chapter 23 Cyanobactin Ribosomally Synthesized Peptides—A Case of Deep Metagenome Mining
book, January 2009

Prenyl transfer to aromatic substrates: genetics and enzymology
journal, April 2009

Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks
journal, November 2003

Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiont of Lissoclinum patella
journal, May 2005

Highly Diverse Cyanobactins in Strains of the Genus Anabaena
journal, December 2009

Protein Prenylation: Enzymes, Therapeutics, and Biotechnology Applications
journal, November 2014

Crystal Structure of Recombinant Farnesyl Diphosphate Synthase at 2.6-.ANG. Resolution
journal, September 1994

The structural biology of patellamide biosynthesis
journal, December 2014

Linking Chemistry and Genetics in the Growing Cyanobactin Natural Products Family
journal, April 2011

Mutagenesis Studies of Protein Farnesyltransferase Implicate Aspartate β352 as a Magnesium Ligand
journal, October 2003

Regulation of peptide antibiotic production in Bacillus
journal, March 1993

Genome Mining Expands the Chemical Diversity of the Cyanobactin Family to Include Highly Modified Linear Peptides
journal, August 2013

Mechanistic studies on the indole prenyltransferases
journal, January 2015

Recent advances in protein prenyltransferases: substrate identification, regulation, and disease interventions
journal, December 2012

Multifunctional Prenylated Peptides for Live Cell Analysis
journal, June 2009

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria
journal, August 2009

Structure and Mechanism of the Magnesium-Independent Aromatic Prenyltransferase CloQ from the Clorobiocin Biosynthetic Pathway
journal, December 2010

Using Marine Natural Products to Discover a Protease that Catalyzes Peptide Macrocyclization of Diverse Substrates
journal, February 2009

A global assembly line for cyanobactins
journal, April 2008

Acein-1, a novel angiotensin-I-converting enzyme inhibitory peptide isolated from tryptic hydrolysate of human plasma
journal, November 1998

Follow the leader: the use of leader peptides to guide natural product biosynthesis
journal, December 2009

Recognition Sequences and Substrate Evolution in Cyanobactin Biosynthesis
journal, March 2014

Converting Peptides into Drug Leads by Lipidation
journal, March 2012

Molecular Insight into the Mg ²⁺ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1
journal, May 2018

Molecular Insight into the Mg ²⁺ -Dependent Allosteric Control of Indole Prenylation by Aromatic Prenyltransferase AmbP1
journal, May 2018

Parallel lives of symbionts and hosts: chemical mutualism in marine animals
journal, January 2018