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Structure of heme transport protein Shr-Linker-NEAT1 from Streptococcus pyogenes in complex with heme.
Structural highlights
FunctionSHR_STRP1 Hemoprotein receptor that plays a central role in the acquisition of host heme, a source of iron during bacterial infection, and is therefore an important virulence factor (PubMed:12595414, PubMed:20807204, PubMed:23076332, PubMed:23993953, PubMed:36693107). Captures host hemoproteins and their iron-containing heme molecules, and transfers the heme to the cell surface heme-binding protein Shp (PubMed:18215300, PubMed:23993953). Plays a pivotal role in iron acquisition and growth under iron-starvation conditions (PubMed:23076332). Uses a cap and release mechanism in which Shr forms a dynamic complex with hemoglobin that enables the gated release of its most labile heme molecule (PubMed:36693107). This mechanism exploits the hemoglobin beta subunit's inherent weaker affinity for heme, allowing S.pyogenes to preferentially capture only heme-saturated forms of hemoglobin that contain iron (PubMed:36693107). In vitro, binds directly to a variety of heme-containing proteins, including hemoglobin, myoglobin, heme albumin and the hemoglobin-haptoglobin complex (PubMed:12595414, PubMed:30301765). It also binds to and acquires heme from methemoglobin, the ferric form of hemoglobin, which is likely to be a physiologically relevant heme source for the hemolytic group A streptococcus (GAS) (PubMed:20807204, PubMed:36693107). Seems to have an inherent ability to reduce the ferric heme present in methemoglobin to ferrous heme and to provide a stable environment for the produced ferrous complex (PubMed:20807204). Does not bind apohemoglobin, apohaptoglobin, fibrinogen or streptavidin, indicating that it specifically recognizes hemoproteins (PubMed:12595414, PubMed:20807204).[1] [2] [3] [4] [5] [6] [7] In addition to its role in heme acquisition, functions as an adhesin, contributing to host cell adhesion and hence virulence (PubMed:18710861). Specifically binds to extracellular matrix (ECM) components, including fibronectin and laminin, and mediates bacterial attachment to host epithelial cells (PubMed:18710861, PubMed:20807204).[8] [9] Publication Abstract from PubMedStreptococcus pyogenes causes a range of infectious diseases. In an era of increasing antibiotic resistance, new antimicrobial strategies targeting virulence factors, rather than essential survival mechanisms, are being explored. A key virulence factor in S. pyogenes is the bacterial iron acquisition system, because iron is essential but limited in the host due to sequestration by proteins like hemoglobin. The bacteria S. pyogenes possesses the Shr protein that acquires heme from host hemoglobin and transfers it to Shp, a membrane proximity protein. Shr comprises multiple domains, including two NEAr-Transporter (NEAT) domains that directly bind to heme. While structural information of NEAT domains from other bacteria are available, the structure of NEAT domains from Shr remains unknown. In this study, crystal structures of Linker-NEAT1 and NEAT2 domains were determined to 2.35 A resolution and 2.66 A resolution, respectively. Structural and mutational analyses revealed that methionine residues play a key role in heme binding, which seems to be a characteristic of heme-binding proteins from S. pyogenes, but not of NEAT domains from other gram-positive species. These findings enhance our understanding of heme acquisition in S. pyogenes and may guide novel therapeutic approaches. Structural basis for heme binding by the Shr protein from Streptococcus pyogenes.,Seki K, Senoo A, Nagatoishi S, Yanaka S, Nakakido M, Tsumoto K, Caaveiro JMM J Biol Chem. 2026 Jan;302(1):111012. doi: 10.1016/j.jbc.2025.111012. Epub 2025 , Dec 5. PMID:41354341[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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