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

DOI:https://doi.org/10.1073/pnas.2211939120· OSTI ID:1916494

Macdonald, Ramsay ^[1]; Mahoney, Brendan J. ^[2]; Soule, Jess ^[1]; Goring, Andrew K. ^[1]; Ford, Jordan ^[1]; Loo, Joseph A. ^[3]; Cascio, Duilio ^[4]; Clubb, Robert T. ^[3]

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1. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095
2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, University of California, Los Angeles-United States Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095
3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, University of California, Los Angeles-United States Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095, Molecular Biology Institute, University of California, Los Angeles, CA 90095
4. University of California, Los Angeles-United States Department of Energy Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095

Streptococcus pyogenes (group A Streptococcus ) is a clinically important microbial pathogen that requires iron in order to proliferate. During infections, S. pyogenes uses the surface displayed Shr receptor to capture human hemoglobin (Hb) and acquires its iron-laden heme molecules. Through a poorly understood mechanism, Shr engages Hb via two structurally unique N-terminal Hb-interacting domains (HID1 and HID2) which facilitate heme transfer to proximal NEAr Transporter (NEAT) domains. Based on the results of X-ray crystallography, small angle X-ray scattering, NMR spectroscopy, native mass spectrometry, and heme transfer experiments, we propose that Shr utilizes a “cap and release” mechanism to gather heme from Hb. In the mechanism, Shr uses the HID1 and HID2 modules to preferentially recognize only heme-loaded forms of Hb by contacting the edges of its protoporphyrin rings. Heme transfer is enabled by significant receptor dynamics within the Shr–Hb complex which function to transiently uncap HID1 from the heme bound to Hb’s β subunit, enabling the gated release of its relatively weakly bound heme molecule and subsequent capture by Shr’s NEAT domains. These dynamics may maximize the efficiency of heme scavenging by S. pyogenes , enabling it to preferentially recognize and remove heme from only heme-loaded forms of Hb that contain iron.

• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: FC02-02ER63421
• OSTI ID: 1916494
• Alternate ID(s): OSTI ID: 2423700
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 5 Vol. 120; ISSN 0027-8424
• Publisher: Proceedings of the National Academy of Sciences
• Country of Publication: United States
• Language: English