Skip to main content
U.S. Department of Energy
Office of Scientific and Technical Information

NEAr Transporter (NEAT) Domains: Unique Surface Displayed Heme Chaperones That Enable Gram-Positive Bacteria to Capture Heme-Iron From Hemoglobin

Journal Article · · Frontiers in Microbiology
 [1];  [2];  [3]
  1. Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry; Univ. of California, Los Angeles, CA (United States). UCLA-DOE Inst. for Genomics and Proteomics; Univ. of California, Los Angeles, CA (United States)
  2. Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry; Univ. of California, Los Angeles, CA (United States). UCLA-DOE Inst. for Genomics and Proteomics
  3. Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry; Univ. of California, Los Angeles, CA (United States). UCLA-DOE Inst. for Genomics and Proteomics; Univ. of California, Los Angeles, CA (United States). Molecular Biology Inst.

Iron is an important micronutrient that is required by bacteria to proliferate and to cause disease. Many bacterial pathogens forage iron from human hemoglobin (Hb) during infections, which contains this metal within heme (iron–protoporphyrin IX). Several clinically important pathogenic species within the Firmicutes phylum scavenge heme using surface-displayed or secreted NEAr Transporter (NEAT) domains. In this review, we discuss how these versatile proteins function in the Staphylococcus aureus Iron-regulated surface determinant system that scavenges heme-iron from Hb. S. aureus NEAT domains function as either Hb receptors or as heme-binding chaperones. In vitro studies have shown that heme-binding NEAT domains can rapidly exchange heme amongst one another via transiently forming transfer complexes, leading to the interesting hypothesis that they may form a protein-wire within the peptidoglycan layer through which heme flows from the microbial surface to the membrane. In Hb receptors, recent studies have revealed how dedicated heme- and Hb-binding NEAT domains function synergistically to extract Hb’s heme molecules, and how receptor binding to the Hb-haptoglobin complex may block its clearance by macrophages, prolonging microbial access to Hb’s iron. The functions of NEAT domains in other Gram-positive bacteria are also reviewed.

Research Organization:
University of California, Los Angeles, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
FC02-02ER63421
OSTI ID:
1849007
Journal Information:
Frontiers in Microbiology, Journal Name: Frontiers in Microbiology Vol. 11; ISSN 1664-302X
Publisher:
Frontiers Research FoundationCopyright Statement
Country of Publication:
United States
Language:
English

References (88)

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism book January 2017
Iron-Coordinating Tyrosine Is a Key Determinant of NEAT Domain Heme Transfer journal October 2011
Unique Heme-Iron Coordination by the Hemoglobin Receptor IsdB of Staphylococcus aureus journal June 2011
Solution Structure and Molecular Determinants of Hemoglobin Binding of the First NEAT Domain of IsdB in Staphylococcus aureus journal June 2014
Heme Binding Properties of Staphylococcus aureus IsdE journal October 2007
Transient Weak Protein–Protein Complexes Transfer Heme Across the Cell Wall of Staphylococcus aureus journal September 2011
Signal peptides direct surface proteins to two distinct envelope locations of Staphylococcus aureus journal September 2008
The theft of host heme by Gram-positive pathogenic bacteria journal January 2011
Heme Transfer to the Bacterial Cell Envelope Occurs via a Secreted Hemophore in the Gram-positive Pathogen Bacillus anthracis journal September 2009
Mapping Ultra-weak Protein-Protein Interactions between Heme Transporters of Staphylococcus aureus journal May 2012
Structure of the Hemoglobin-IsdH Complex Reveals the Molecular Basis of Iron Capture by Staphylococcus aureus journal January 2014
The Staphylococcus aureus Protein IsdH Inhibits Host Hemoglobin Scavenging to Promote Heme Acquisition by the Pathogen journal September 2016
The IsdC Protein from Staphylococcus aureus Uses a Flexible Binding Pocket to Capture Heme journal August 2008
The human protein haptoglobin inhibits IsdH-mediated heme-sequestering by Staphylococcus aureus journal February 2020
Protein secretion and surface display in Gram-positive bacteria journal April 2012
The structure of haemoglobin bound to the haemoglobin receptor IsdH from Staphylococcus aureus shows disruption of the native α-globin haem pocket journal May 2015
Haem recognition by a Staphylococcus aureus NEAT domain journal January 2007
Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus journal May 2009
Passage of Heme-Iron Across the Envelope of Staphylococcus aureus journal February 2003
An Iron-Regulated Autolysin Remodels the Cell Wall To Facilitate Heme Acquisition in Staphylococcus lugdunensis journal September 2015
Sequestration and Scavenging of Iron in Infection journal July 2013
Identification and Characterization of a Streptococcus pyogenes Operon Involved in Binding of Hemoproteins and Acquisition of Iron journal March 2003
Hal Is a Bacillus anthracis Heme Acquisition Protein journal August 2012
Refining Our Perception of Bacterial Surfaces with the Atomic Force Microscope journal June 2004
Molecular Basis for the Evolution of Species-Specific Hemoglobin Capture by Staphylococcus aureus journal December 2018
Extracellular Heme Uptake and the Challenge of Bacterial Cell Membranes journal June 2017
Three-dimensional structure of the bacterial cell wall peptidoglycan dataset January 2006
Molecular and Evolutionary Analysis of NEAr-Iron Transporter (NEAT) Domains journal August 2014
Bacillus anthracis Secretes Proteins That Mediate Heme Acquisition from Hemoglobin journal August 2008
Differential Function of Lip Residues in the Mechanism and Biology of an Anthrax Hemophore journal March 2012
Role and regulation of heme iron acquisition in gram-negative pathogens journal January 2013
Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus : Recognition of Antimicrobial Porphyrins by IsdH-NEAT3 journal June 2013
NMR experiments redefine the hemoglobin binding properties of bacterial NEAr‐iron Transporter domains journal July 2019
Heme binding to the IsdE(M78A; H229A) double mutant: challenging unidirectional heme transfer in the iron-regulated surface determinant protein heme transfer pathway of Staphylococcus aureus journal June 2012
Staphylococcus aureus heme and siderophore-iron acquisition pathways journal March 2019
His64(E7)–>Tyr apomyoglobin as a reagent for measuring rates of hemin dissociation. journal February 1994
Heme uptake in bacterial pathogens journal April 2014
A Staphylococcus aureus Regulatory System that Responds to Host Heme and Modulates Virulence journal April 2007
Specificity for Human Hemoglobin Enhances Staphylococcus aureus Infection journal December 2010
Handling heme: The mechanisms underlying the movement of heme within and between cells journal March 2019
Solution Structure of the NEAT (NEAr Transporter) Domain from IsdH/HarA: the Human Hemoglobin Receptor in Staphylococcus aureus journal July 2006
The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin journal March 2016
Heme Synthesis and Acquisition in Bacterial Pathogens journal August 2016
The Staphylococcus aureus IsdH Receptor Forms a Dynamic Complex with Human Hemoglobin that Triggers Heme Release via Two Distinct Hot Spots journal February 2020
Molecular Basis of Recognition of Antibacterial Porphyrins by Heme-Transporter IsdH-NEAT3 of Staphylococcus aureus journal August 2011
Heme Binding Mechanism of Structurally Similar Iron-Regulated Surface Determinant Near Transporter Domains of Staphylococcus aureus Exhibiting Different Affinities for Heme journal November 2013
Hemoglobin Binding and Catalytic Heme Extraction by IsdB Near Iron Transporter Domains journal April 2014
Multiprotein Heme Shuttle Pathway in Staphylococcus aureus : Iron-Regulated Surface Determinant Cog-Wheel Kinetics journal October 2012
Identification of the haemoglobin scavenger receptor journal January 2001
Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system journal November 2014
Iron and zinc exploitation during bacterial pathogenesis journal January 2015
Identification of a novel iron regulated staphylococcal surface protein with haptoglobin-haemoglobin binding activity: Staphylococcal haptoglobin receptor journal May 2003
Three-dimensional structure of the bacterial cell wall peptidoglycan journal March 2006
The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC journal August 2011
Structural Basis for Hemoglobin Capture by Staphylococcus aureus Cell-surface Protein, IsdH journal September 2011
Staphylococcus aureus Uses a Novel Multidomain Receptor to Break Apart Human Hemoglobin and Steal Its Heme journal November 2012
The Near-iron Transporter (NEAT) Domains of the Anthrax Hemophore IsdX2 Require a Critical Glutamine to Extract Heme from Methemoglobin journal March 2013
CD163 Binding to Haptoglobin-Hemoglobin Complexes Involves a Dual-point Electrostatic Receptor-Ligand Pairing journal June 2013
Novel Mechanism of Hemin Capture by Hbp2, the Hemoglobin-binding Hemophore from Listeria monocytogenes journal October 2014
Structure–function analyses reveal key features in Staphylococcus aureus IsdB-associated unfolding of the heme-binding pocket of human hemoglobin journal November 2017
Staphylococcus aureus IsdG and IsdI, Heme-degrading Enzymes with Structural Similarity to Monooxygenases journal October 2004
Anchor Structure of Staphylococcal Surface Proteins journal April 2005
The Mechanism of Direct Heme Transfer from the Streptococcal Cell Surface Protein Shp to HtsA of the HtsABC Transporter journal May 2006
Crystal Structure of the Heme-IsdC Complex, the Central Conduit of the Isd Iron/Heme Uptake System in Staphylococcus aureus journal February 2007
Direct Hemin Transfer from IsdA to IsdC in the Iron-regulated Surface Determinant (Isd) Heme Acquisition System of Staphylococcus aureus journal January 2008
Pathway for Heme Uptake from Human Methemoglobin by the Iron-regulated Surface Determinants System of Staphylococcus aureus journal June 2008
Structural Basis for Multimeric Heme Complexation through a Specific Protein-Heme Interaction journal July 2008
Functionally Distinct NEAT (NEAr Transporter) Domains within the Staphylococcus aureus IsdH/HarA Protein Extract Heme from Methemoglobin journal November 2008
Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus journal March 2018
The iron-regulated surface determinant B (IsdB) protein from Staphylococcus aureus acts as a receptor for the host protein vitronectin journal July 2020
Recent developments in understanding the iron acquisition strategies of gram positive pathogens journal April 2015
IsdB-dependent Hemoglobin Binding Is Required for Acquisition of Heme by Staphylococcus aureus journal December 2013
The structure of α-haemoglobin in complex with a haemoglobin-binding domain from Staphylococcus aureus reveals the elusive α-haemoglobin dimerization interface journal July 2014
IsdA of Staphylococcus aureus is a broad spectrum, iron-regulated adhesin: Staphylococcus aureus adhesin journal February 2004
The svpA-srtB locus of Listeria monocytogenes: Fur-mediated iron regulation and effect on virulence: The svpA-srtB locus of Listeria journal December 2004
Shr of group A streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin: Haem uptake and reduction by Shr journal September 2010
Subcellular Localization of the Staphylococcus aureus Heme Iron Transport Components IsdA and IsdB journal April 2009
Heme Transfer from Streptococcal Cell Surface Protein Shp to HtsA of Transporter HtsABC journal July 2005
A Bacillus anthracis S-Layer Homology Protein That Binds Heme and Mediates Heme Delivery to IsdC journal April 2010
Staphylococcus aureus IsdB Is a Hemoglobin Receptor Required for Heme Iron Utilization journal October 2006
High-Affinity Binding of the Staphylococcal HarA Protein to Haptoglobin and Hemoglobin Involves a Domain with an Antiparallel Eight-Stranded  -Barrel Fold journal October 2006
Atomic Force Microscopy of Cell Growth and Division in Staphylococcus aureus journal June 2004
Molecular Basis for the Evolution of Species-Specific Hemoglobin Capture by Staphylococcus aureus journal December 2018
Iron Acquisition Strategies of Bacterial Pathogens journal March 2016
The surface protein Shr of Streptococcus pyogenes binds heme and transfers it to the streptococcal heme-binding protein Shp journal January 2008
Purification and Structural Characterization of Siderophore (Corynebactin) from Corynebacterium diphtheriae journal April 2012
Rapid Heme Transfer Reactions between NEAr Transporter Domains of Staphylococcus aureus: A Theoretical Study Using QM/MM and MD Simulations journal December 2015
IlsA, A Unique Surface Protein of Bacillus cereus Required for Iron Acquisition from Heme, Hemoglobin and Ferritin journal November 2009

Similar Records

The Shr receptor from Streptococcus pyogenes uses a cap and release mechanism to acquire heme–iron from human hemoglobin
Journal Article · Mon Jan 23 23:00:00 EST 2023 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1916494

Haem Recognition By a Staphylococcus Aureus NEAT Domain
Journal Article · Mon Jun 01 00:00:00 EDT 2009 · Mol. Microbiol. 63:139,2007 · OSTI ID:953986