Structural basis for iron piracy by pathogenic neisseria

ABSTRACT _Neisseria_ are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. _Neisseria_ require iron for survival and can extract it directly from human

transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both

proteins are potentially important vaccine and therapeutic targets. Two key questions driving _Neisseria_ research are how human transferrin is specifically targeted, and how the bacteria

liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA–transferrin complex and of the corresponding co-receptor TbpB. We

characterized the TbpB–transferrin complex by small-angle X-ray scattering and the TbpA–TbpB–transferrin complex by electron microscopy. Our studies provide a rational basis for the

specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process. Access through your institution Buy or

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TDFH SELECTIVELY BINDS METAL-LOADED TETRAMERIC CALPROTECTIN FOR ZINC IMPORT Article Open access 31 January 2022 AVAILABILITY OF IRON IONS IMPACTS PHYSICOCHEMICAL PROPERTIES AND PROTEOME OF

OUTER MEMBRANE VESICLES RELEASED BY _NEISSERIA GONORRHOEAE_ Article Open access 31 October 2023 ALLOSTERIC SUBSTRATE RELEASE BY A SIALIC ACID TRAP TRANSPORTER SUBSTRATE BINDING PROTEIN

Article Open access 23 November 2024 ACCESSION CODES PRIMARY ACCESSIONS PROTEIN DATA BANK * 3SKP * 3V83 * 3V89 * 3V8U * 3V8X DATA DEPOSITS Coordinates and structure factors for

TbpA–(apo)hTF, TbpA–(apo)hTF C lobe, diferric hTF, apo-hTF C lobe and TbpB are deposited in the Protein Data Bank under accession codes 3V8X, 3V89, 3V83, 3SKP and 3V8U, respectively.

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  PubMed Central  Google Scholar  Download references ACKNOWLEDGEMENTS N.N., N.C.E., M.O., E.B. and S.K.B. are supported by the Intramural Research Program of the NIH, National Institute of

Diabetes and Digestive and Kidney Diseases. M.O. was initially funded by an EPSRC Research Committee Studentship awarded to S.K.B. and R.W.E. N.M. and A.C.S. are supported by the Intramural

Research Program of the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases. A.B.M. was supported in part by USPHS grant R01-DK21739. A.N.S. is funded by an AHA

Predoctoral Fellowship (10PRE4200010). E.T. acknowledges NIH support by R01-GM086749, U54-GM087519 and P41-RR05969. All the simulations were performed using TeraGrid resources (MCA06N060).

We thank the respective staffs at the Southeast Regional Collaborative Access Team (SER-CAT) and General Medicine and Cancer Institutes Collaborative Access Team (GM/CA-CAT) beamlines at the

Advanced Photon Source, Argonne National Laboratory for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of

Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38 (SER-CAT), and by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No.

DE-AC02-06CH11357 (GM/CA-CAT). Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf

of the US Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and

Environmental Research, and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, 20892, Maryland, USA Nicholas Noinaj, Nicole C.

Easley, Muse Oke, Evzen Boura & Susan K. Buchanan * Laboratory of Structural Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of

Health, Bethesda, 20892, Maryland, USA Naoko Mizuno & Alasdair C. Steven * Biosciences Division, Argonne National Laboratory, Argonne, 60439, Illinois, USA James Gumbart * Department of

Biochemistry, University of Vermont, College of Medicine, 89 Beaumont Avenue, Burlington, Vermont 05405, USA, Ashley N. Steere & Anne B. Mason * Albert Einstein College of Medicine, 1300

Morris Park Avenue, Bronx, New York 10461, USA, Olga Zak & Philip Aisen * Department of Biochemistry and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, 61801,

Illinois, USA Emad Tajkhorshid * Division of Biosciences, Metalloprotein Research Group, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex UB8 3PH, UK, Robert

W. Evans * Health Protection Agency, Porton Down, Salisbury SP2 8NY, UK, Andrew R. Gorringe Authors * Nicholas Noinaj View author publications You can also search for this author inPubMed 

Google Scholar * Nicole C. Easley View author publications You can also search for this author inPubMed Google Scholar * Muse Oke View author publications You can also search for this author

inPubMed Google Scholar * Naoko Mizuno View author publications You can also search for this author inPubMed Google Scholar * James Gumbart View author publications You can also search for

this author inPubMed Google Scholar * Evzen Boura View author publications You can also search for this author inPubMed Google Scholar * Ashley N. Steere View author publications You can

also search for this author inPubMed Google Scholar * Olga Zak View author publications You can also search for this author inPubMed Google Scholar * Philip Aisen View author publications

You can also search for this author inPubMed Google Scholar * Emad Tajkhorshid View author publications You can also search for this author inPubMed Google Scholar * Robert W. Evans View

author publications You can also search for this author inPubMed Google Scholar * Andrew R. Gorringe View author publications You can also search for this author inPubMed Google Scholar *

Anne B. Mason View author publications You can also search for this author inPubMed Google Scholar * Alasdair C. Steven View author publications You can also search for this author inPubMed 

Google Scholar * Susan K. Buchanan View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS N.N., N.C.E., M.O. and S.K.B. expressed, purified and

crystallized TbpA, TbpB and various hTFs. N.N. solved all crystal structures and the SAXS structure and analysed all data. A.B.M. and A.N.S. designed and purified apo-hTF, holo-hTF, hTF–FeN

and hTF–FeC for binding experiments with TbpA and TbpB; they also expressed and purified hTF C lobe for the corresponding structure (PDB code 3SKP). P.A. and O.Z. expressed and purified hTF

C lobe for the TbpA–(apo)hTF C-lobe structure (PDB code 3V89). N.M. and A.C.S. designed, conducted and analysed EM experiments. E.T. and J.G. designed, conducted and analysed molecular

dynamics simulations. E.B. participated in the data collection and analysis of the SAXS data. R.W.E., A.R.G. and S.K.B. conceived and designed the original project. N.N. and S.K.B. wrote the

manuscript. CORRESPONDING AUTHOR Correspondence to Susan K. Buchanan. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION This file contains Supplementary Figures 1-18 with legends, Supplementary Tables 1-4, full legends for Supplementary Movies 1-2 and additional references. (PDF

28815 kb) SUPPLEMENTARY MOVIE 1 The movie shows the molecular dynamics simulation of the TbpA-TonB interaction (see Supplementary Information file for full legend). (MOV 19599 kb)

SUPPLEMENTARY MOVIE 2 The movie shows the iron import machinery from pathogenic _Neisseria_ (see Supplementary Information file for full legend). (MOV 29868 kb) POWERPOINT SLIDES POWERPOINT

SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Noinaj, N., Easley, N., Oke, M. _et al._ Structural basis for iron piracy by pathogenic _Neisseria_. _Nature_ 483, 53–58 (2012). https://doi.org/10.1038/nature10823

Download citation * Received: 19 September 2011 * Accepted: 09 January 2012 * Published: 12 February 2012 * Issue Date: 01 March 2012 * DOI: https://doi.org/10.1038/nature10823 SHARE THIS

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