Molecular Cross-Talk between Nonribosomal Peptide Synthetase Carrier Proteins and Unstructured Linker Regions

Bradley J. Harden, Dominique P. Frueh

Research output: Contribution to journalArticle

Abstract

Nonribosomal peptide synthetases (NRPSs) employ multiple domains separated by linker regions to incorporate substrates into natural products. During synthesis, substrates are covalently tethered to carrier proteins that translocate between catalytic partner domains. The molecular parameters that govern translocation and associated linker remodeling remain unknown. Here, we used NMR to characterize the structure, dynamics, and invisible states of a peptidyl carrier protein flanked by its linkers. We showed that the N-terminal linker stabilizes and interacts with the protein core while modulating dynamics at specific sites involved in post-translational modifications and/or domain interactions. The results detail the molecular communication between peptidyl carrier proteins and their linkers and could guide efforts in engineering NRPSs to obtain new pharmaceuticals.

LanguageEnglish (US)
Pages629-632
Number of pages4
JournalChemBioChem
Volume18
Issue number7
DOIs
StatePublished - Apr 4 2017

Fingerprint

Peptide Synthases
Carrier Proteins
Substrates
Post Translational Protein Processing
Biological Products
Catalytic Domain
Nuclear magnetic resonance
Communication
Pharmaceutical Preparations
Proteins

Keywords

  • allostery
  • nonribosomal peptide synthetase
  • nuclear magnetic resonance
  • protein dynamics
  • protein folding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

Molecular Cross-Talk between Nonribosomal Peptide Synthetase Carrier Proteins and Unstructured Linker Regions. / Harden, Bradley J.; Frueh, Dominique P.

In: ChemBioChem, Vol. 18, No. 7, 04.04.2017, p. 629-632.

Research output: Contribution to journalArticle

@article{63c8a97159524e61b660e5ce0cf99a35,
title = "Molecular Cross-Talk between Nonribosomal Peptide Synthetase Carrier Proteins and Unstructured Linker Regions",
abstract = "Nonribosomal peptide synthetases (NRPSs) employ multiple domains separated by linker regions to incorporate substrates into natural products. During synthesis, substrates are covalently tethered to carrier proteins that translocate between catalytic partner domains. The molecular parameters that govern translocation and associated linker remodeling remain unknown. Here, we used NMR to characterize the structure, dynamics, and invisible states of a peptidyl carrier protein flanked by its linkers. We showed that the N-terminal linker stabilizes and interacts with the protein core while modulating dynamics at specific sites involved in post-translational modifications and/or domain interactions. The results detail the molecular communication between peptidyl carrier proteins and their linkers and could guide efforts in engineering NRPSs to obtain new pharmaceuticals.",
keywords = "allostery, nonribosomal peptide synthetase, nuclear magnetic resonance, protein dynamics, protein folding",
author = "Harden, {Bradley J.} and Frueh, {Dominique P.}",
year = "2017",
month = "4",
day = "4",
doi = "10.1002/cbic.201700030",
language = "English (US)",
volume = "18",
pages = "629--632",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",
number = "7",

}

TY - JOUR

T1 - Molecular Cross-Talk between Nonribosomal Peptide Synthetase Carrier Proteins and Unstructured Linker Regions

AU - Harden,Bradley J.

AU - Frueh,Dominique P.

PY - 2017/4/4

Y1 - 2017/4/4

N2 - Nonribosomal peptide synthetases (NRPSs) employ multiple domains separated by linker regions to incorporate substrates into natural products. During synthesis, substrates are covalently tethered to carrier proteins that translocate between catalytic partner domains. The molecular parameters that govern translocation and associated linker remodeling remain unknown. Here, we used NMR to characterize the structure, dynamics, and invisible states of a peptidyl carrier protein flanked by its linkers. We showed that the N-terminal linker stabilizes and interacts with the protein core while modulating dynamics at specific sites involved in post-translational modifications and/or domain interactions. The results detail the molecular communication between peptidyl carrier proteins and their linkers and could guide efforts in engineering NRPSs to obtain new pharmaceuticals.

AB - Nonribosomal peptide synthetases (NRPSs) employ multiple domains separated by linker regions to incorporate substrates into natural products. During synthesis, substrates are covalently tethered to carrier proteins that translocate between catalytic partner domains. The molecular parameters that govern translocation and associated linker remodeling remain unknown. Here, we used NMR to characterize the structure, dynamics, and invisible states of a peptidyl carrier protein flanked by its linkers. We showed that the N-terminal linker stabilizes and interacts with the protein core while modulating dynamics at specific sites involved in post-translational modifications and/or domain interactions. The results detail the molecular communication between peptidyl carrier proteins and their linkers and could guide efforts in engineering NRPSs to obtain new pharmaceuticals.

KW - allostery

KW - nonribosomal peptide synthetase

KW - nuclear magnetic resonance

KW - protein dynamics

KW - protein folding

UR - http://www.scopus.com/inward/record.url?scp=85013657513&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013657513&partnerID=8YFLogxK

U2 - 10.1002/cbic.201700030

DO - 10.1002/cbic.201700030

M3 - Article

VL - 18

SP - 629

EP - 632

JO - ChemBioChem

T2 - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 7

ER -