scholarly journals The inherent flexibility of type I non-ribosomal peptide synthetase multienzymes drives their catalytic activities

Open Biology ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 200386
Author(s):  
Sarah Bonhomme ◽  
Andréa Dessen ◽  
Pauline Macheboeuf
Keyword(s):  
Protein Domains ◽  
Bioactive Metabolites ◽  
Carrier Protein ◽  
Type I ◽  
Peptide Synthetases ◽  
Catalytic Domains ◽  
Large Size ◽  
Peptide Synthetase ◽  
Modify Amino Acid ◽  
Conformational Rearrangements

Non-ribosomal peptide synthetases (NRPSs) are multienzymes that produce complex natural metabolites with many applications in medicine and agriculture. They are composed of numerous catalytic domains that elongate and chemically modify amino acid substrates or derivatives and of non-catalytic carrier protein domains that can tether and shuttle the growing products to the different catalytic domains. The intrinsic flexibility of NRPSs permits conformational rearrangements that are required to allow interactions between catalytic and carrier protein domains. Their large size coupled to this flexibility renders these multi-domain proteins very challenging for structural characterization. Here, we summarize recent studies that offer structural views of multi-domain NRPSs in various catalytically relevant conformations, thus providing an increased comprehension of their catalytic cycle. A better structural understanding of these multienzymes provides novel perspectives for their re-engineering to synthesize new bioactive metabolites.

Characterization of Sfp, aBacillus subtilisPhosphopantetheinyl Transferase for Peptidyl Carrier Protein Domains in Peptide Synthetases†

Biochemistry ◽  
1998 ◽  
Vol 37 (6) ◽  
pp. 1585-1595 ◽  
Author(s):  
Luis E. N. Quadri ◽  
Paul H. Weinreb ◽  
Ming Lei ◽  
Michiko M. Nakano ◽  
Peter Zuber ◽  
...  
Keyword(s):  
Protein Domains ◽  
Carrier Protein ◽  
Peptide Synthetases

scholarly journals Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luisa Moretto ◽  
Rachel Heylen ◽  
Natalie Holroyd ◽  
Steven Vance ◽  
R. William Broadhurst
Keyword(s):  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Protein Domains ◽  
Carrier Protein ◽  
Type I

scholarly journals Structure of PA1221, a Nonribosomal Peptide Synthetase Containing Adenylation and Peptidyl Carrier Protein Domains

Biochemistry ◽  
2012 ◽  
Vol 51 (15) ◽  
pp. 3252-3263 ◽  
Author(s):  
Carter A. Mitchell ◽  
Ce Shi ◽  
Courtney C. Aldrich ◽  
Andrew M. Gulick
Keyword(s):  
Protein Domains ◽  
Nonribosomal Peptide Synthetase ◽  
Carrier Protein ◽  
Nonribosomal Peptide ◽  
Peptide Synthetase

scholarly journals Intermediary conformations linked to the directionality of the aminoacylation pathway of nonribosomal peptide synthetases

2021 ◽  
Author(s):  
Florian Mayerthaler ◽  
Anna-Lena Feldberg ◽  
Jonas Alfermann ◽  
Xun Sun ◽  
Wieland Steinchen ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Domains ◽  
Carrier Protein ◽  
Nonribosomal Peptide ◽  
Nonribosomal Peptide Synthetases ◽  
Peptide Synthetases

In-solution analysis of conformational changes of NRPS adenylation and peptidyl-carrier protein domains under catalytic conditions reveals a new intermediary conformation.

scholarly journals Molecular Basis for Acyl Carrier Protein-Ketoreductase Interaction in trans-Acyltransferase Polyketide Synthases

2021 ◽  
Author(s):  
Munro Passmore ◽  
Angelo Gallo ◽  
Józef Romuald Lewandowski ◽  
Matthew Jenner
Keyword(s):  
Molecular Basis ◽  
Acyl Carrier Protein ◽  
Polyketide Synthases ◽  
Carrier Protein ◽  
Type I ◽  
Catalytic Domains ◽  
In Trans

The biosynthesis of polyketides by type I modular polyketide synthases (PKS) relies on co-ordinated interactions between acyl carrier protein (ACP) domains and catalytic domains within the megasynthase. Despite the importance...

scholarly journals Structural and bioinformatic characterization of anAcinetobacter baumanniitype II carrier protein

2014 ◽  
Vol 70 (6) ◽  
pp. 1718-1725 ◽  
Author(s):  
C. Leigh Allen ◽  
Andrew M. Gulick
Keyword(s):  
Protein Domain ◽  
Carrier Protein ◽  
Free Standing ◽  
Peptide Synthetases ◽  
Catalytic Domains ◽  
Single Protein ◽  
Domain Interactions ◽  
Partner Proteins ◽  
Precise Role

Microorganisms produce a variety of natural productsviasecondary metabolic biosynthetic pathways. Two of these types of synthetic systems, the nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), use large modular enzymes containing multiple catalytic domains in a single protein. These multidomain enzymes use an integrated carrier protein domain to transport the growing, covalently bound natural product to the neighboring catalytic domains for each step in the synthesis. Interestingly, some PKS and NRPS clusters contain free-standing domains that interact intermolecularly with other proteins. Being expressed outside the architecture of a multi-domain protein, these so-called type II proteins present challenges to understand the precise role they play. Additional structures of individual and multi-domain components of the NRPS enzymes will therefore provide a better understanding of the features that govern the domain interactions in these interesting enzyme systems. The high-resolution crystal structure of a free-standing carrier protein fromAcinetobacter baumanniithat belongs to a larger NRPS-containing operon, encoded by the ABBFA_003406–ABBFA_003399 genes ofA. baumanniistrain AB307-0294, that has been implicated inA. baumanniimotility, quorum sensing and biofilm formation, is presented here. Comparison with the closest structural homologs of other carrier proteins identifies the requirements for a conserved glycine residue and additional important sequence and structural requirements within the regions that interact with partner proteins.

scholarly journals Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joanna L. Fox ◽  
Michelle A. Hughes ◽  
Xin Meng ◽  
Nikola A. Sarnowska ◽  
Ian R. Powley ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Analysis ◽  
Cell Fate ◽  
Catalytic Domain ◽  
Caspase 8 ◽  
Type I ◽  
Signaling Complex ◽  
Catalytic Domains ◽  
Regulated Cell Death ◽  
Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

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