{"entity": "researcher", "timestamp": "2026-07-19T06:36:09.653Z", "family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "affiliations": ["Department of Clinical Sciences , Lund University , Lund , Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe"}}, "publications": [{"entity": "publication", "iuid": "4511a6759a1f496e8c06555aa49190df", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4511a6759a1f496e8c06555aa49190df.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4511a6759a1f496e8c06555aa49190df"}}, "title": "Design of a Streptolysin O Epitope-Centric Nanoparticle Vaccine Against Streptococcus pyogenes", "authors": [{"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Chao", "given": "Yashuan", "initials": "Y", "orcid": "0000-0002-0295-3142", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed7bd7c821754977ba516c3e1c04eceb.json"}}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E", "orcid": "0009-0003-9932-1751", "researcher": {"href": "https://publications.scilifelab.se/researcher/2fcf5002d49b458f81cea775594e63fb.json"}}, {"family": "Str\u00f6baek", "given": "Joel", "initials": "J", "orcid": "0000-0003-1231-0420", "researcher": {"href": "https://publications.scilifelab.se/researcher/c8d9f6cfe0e845d0a4208d442e4b652c.json"}}, {"family": "Hultgren", "given": "Lucas", "initials": "L"}, {"family": "Mohanty", "given": "Tirthankar", "initials": "T", "orcid": "0000-0003-4593-9612", "researcher": {"href": "https://publications.scilifelab.se/researcher/0a9c51697d33414f8197c7833d9dcc04.json"}}, {"family": "Karlsson", "given": "Christofer", "initials": "C", "orcid": "0000-0002-7099-0092", "researcher": {"href": "https://publications.scilifelab.se/researcher/ef353abbc90943218c194ccdd2bbdb52.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Shannon", "given": "Oonagh", "initials": "O", "orcid": "0000-0001-8291-8189", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed4685bab7584028a070fc5a829bd386.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L"}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "posted-content", "published": "2025-05-28", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2025.05.25.655993", "pmid": null, "labels": {"Cryo-EM": "Service"}, "xrefs": [], "notes": [], "created": "2025-11-13T14:22:08.439Z", "modified": "2025-12-18T19:15:21.994Z"}, {"entity": "publication", "iuid": "be1ccad457054a6ca82002c69b0dacdb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/be1ccad457054a6ca82002c69b0dacdb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/be1ccad457054a6ca82002c69b0dacdb"}}, "title": "Streptolysin O accelerates the conversion of plasminogen to plasmin", "authors": [{"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Khakzad", "given": "Hamed", "initials": "H", "orcid": "0000-0002-8556-0650", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7b030c1452c4dc9b430deffdf493e6f.json"}}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E"}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S", "orcid": "0000-0002-7694-285X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6416b323664f4126b70067193d7b8347.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "journal-article", "published": "2024-11-25", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723", "volume": "15", "issue": "1", "pages": "10212"}, "abstract": "Group A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity.", "doi": "10.1038/s41467-024-54173-6", "pmid": "39587097", "labels": {"Structural Proteomics": "Technology development"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-024-54173-6"}, {"db": "pmc", "key": "PMC11589678"}], "notes": [], "created": "2024-11-27T17:20:53.877Z", "modified": "2024-11-28T17:40:23.904Z"}, {"entity": "publication", "iuid": "561c1367fa4c47edb3391e98dc896b3a", "links": {"self": {"href": "https://publications.scilifelab.se/publication/561c1367fa4c47edb3391e98dc896b3a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/561c1367fa4c47edb3391e98dc896b3a"}}, "title": "Multimodal Mass Spectrometry Identifies a Conserved Protective Epitope in S. pyogenes Streptolysin O", "authors": [{"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Gueto-Tettay", "given": "Carlos", "initials": "C", "orcid": "0000-0002-8496-6341", "researcher": {"href": "https://publications.scilifelab.se/researcher/b0e4a5377a88414588686e5630b0be66.json"}}, {"family": "Hjortswang", "given": "Elisabeth", "initials": "E", "orcid": "0009-0003-9932-1751", "researcher": {"href": "https://publications.scilifelab.se/researcher/2fcf5002d49b458f81cea775594e63fb.json"}}, {"family": "Str\u00f6baek", "given": "Joel", "initials": "J", "orcid": "0000-0003-1231-0420", "researcher": {"href": "https://publications.scilifelab.se/researcher/c8d9f6cfe0e845d0a4208d442e4b652c.json"}}, {"family": "Ekstr\u00f6m", "given": "Simon", "initials": "S"}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}], "type": "journal-article", "published": "2024-06-04", "journal": {"title": "Anal. Chem.", "issn": "0003-2700", "issn-l": null, "volume": "96", "issue": "22", "pages": "9060-9068"}, "abstract": null, "doi": "10.1021/acs.analchem.4c00596", "pmid": null, "labels": {"Structural Proteomics": "Technology development"}, "xrefs": [], "notes": [], "created": "2024-01-16T08:21:27.936Z", "modified": "2024-10-01T09:37:06.467Z"}, {"entity": "publication", "iuid": "b2a30a6011bb47659582e0b4cdce2803", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b2a30a6011bb47659582e0b4cdce2803.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b2a30a6011bb47659582e0b4cdce2803"}}, "title": "The hinge-engineered IgG1-IgG3 hybrid subclass IgGh47 potently enhances Fc-mediated function of anti-streptococcal and SARS-CoV-2 antibodies.", "authors": [{"family": "Izadi", "given": "Arman", "initials": "A", "orcid": "0000-0002-0262-1017", "researcher": {"href": "https://publications.scilifelab.se/researcher/2d6f1927cfc643818a0a3a1b8602af14.json"}}, {"family": "Karami", "given": "Yasaman", "initials": "Y", "orcid": "0000-0001-8413-2665", "researcher": {"href": "https://publications.scilifelab.se/researcher/a71f08b3f3794e66b7adae400c14f142.json"}}, {"family": "Bratanis", "given": "Eleni", "initials": "E", "orcid": "0000-0002-0636-6658", "researcher": {"href": "https://publications.scilifelab.se/researcher/c935953f81fc4d8eb6a9b9ddb7774c1b.json"}}, {"family": "Wrighton", "given": "Sebastian", "initials": "S", "orcid": "0000-0002-3378-7925", "researcher": {"href": "https://publications.scilifelab.se/researcher/0b5821cc01364325a4b9fe177e7f6e33.json"}}, {"family": "Khakzad", "given": "Hamed", "initials": "H", "orcid": "0000-0002-8556-0650", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7b030c1452c4dc9b430deffdf493e6f.json"}}, {"family": "Nyblom", "given": "Maria", "initials": "M"}, {"family": "Olofsson", "given": "Berit", "initials": "B", "orcid": "0009-0009-0602-2183", "researcher": {"href": "https://publications.scilifelab.se/researcher/9ad483473b044b7dbc7e6c61ef1c0a73.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Sundwall", "given": "Martin", "initials": "M", "orcid": "0000-0002-0114-6613", "researcher": {"href": "https://publications.scilifelab.se/researcher/fc0080c10aa64cd7b073813c8ebc0bc7.json"}}, {"family": "Godzwon", "given": "Magdalena", "initials": "M"}, {"family": "Chao", "given": "Yashuan", "initials": "Y", "orcid": "0000-0002-0295-3142", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed7bd7c821754977ba516c3e1c04eceb.json"}}, {"family": "Toledo", "given": "Alejandro Gomez", "initials": "AG", "orcid": "0000-0002-2103-7158", "researcher": {"href": "https://publications.scilifelab.se/researcher/9e9d9a5e2dc148c9bcdc07f2b4a17ebc.json"}}, {"family": "Schmidt", "given": "Tobias", "initials": "T", "orcid": "0000-0001-9943-4121", "researcher": {"href": "https://publications.scilifelab.se/researcher/2eba2593dde24540a7d70aa3b593e4fc.json"}}, {"family": "Ohlin", "given": "Mats", "initials": "M", "orcid": "0000-0002-5105-1938", "researcher": {"href": "https://publications.scilifelab.se/researcher/fda1d1ed0b074a04a69b0c8b036dd001.json"}}, {"family": "Nilges", "given": "Michael", "initials": "M", "orcid": "0000-0002-1451-8092", "researcher": {"href": "https://publications.scilifelab.se/researcher/ebfd5336137d4eaabde8f4f9baed470a.json"}}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}, {"family": "Bahnan", "given": "Wael", "initials": "W"}, {"family": "Shannon", "given": "Oonagh", "initials": "O", "orcid": "0000-0001-8291-8189", "researcher": {"href": "https://publications.scilifelab.se/researcher/ed4685bab7584028a070fc5a829bd386.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Nordenfelt", "given": "Pontus", "initials": "P", "orcid": "0000-0002-9481-9951", "researcher": {"href": "https://publications.scilifelab.se/researcher/7aa3418ab23a4ec48c037d6d6ddea5b5.json"}}], "type": "journal article", "published": "2024-04-27", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "3600", "issn-l": "2041-1723"}, "abstract": "Streptococcus pyogenes can cause invasive disease with high mortality despite adequate antibiotic treatments. To address this unmet need, we have previously generated an opsonic IgG1 monoclonal antibody, Ab25, targeting the bacterial M protein. Here, we engineer the IgG2-4 subclasses of Ab25. Despite having reduced binding, the IgG3 version promotes stronger phagocytosis of bacteria. Using atomic simulations, we show that IgG3's Fc tail has extensive movement in 3D space due to its extended hinge region, possibly facilitating interactions with immune cells. We replaced the hinge of IgG1 with four different IgG3-hinge segment subclasses, IgGhxx. Hinge-engineering does not diminish binding as with IgG3 but enhances opsonic function, where a 47 amino acid hinge is comparable to IgG3 in function. IgGh47 shows improved protection against S. pyogenes in a systemic infection mouse model, suggesting that IgGh47 has promise as a preclinical therapeutic candidate. Importantly, the enhanced opsonic function of IgGh47 is generalizable to diverse S. pyogenes strains from clinical isolates. We generated IgGh47 versions of anti-SARS-CoV-2 mAbs to broaden the biological applicability, and these also exhibit strongly enhanced opsonic function compared to the IgG1 subclass. The improved function of the IgGh47 subclass in two distant biological systems provides new insights into antibody function.", "doi": "10.1038/s41467-024-47928-8", "pmid": "38678029", "labels": {"Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11055898"}, {"db": "pii", "key": "10.1038/s41467-024-47928-8"}], "notes": [], "created": "2024-11-08T09:49:22.468Z", "modified": "2025-10-17T13:05:07.370Z"}, {"entity": "publication", "iuid": "598feb16626f43cdb791a3f07b3a488b", "links": {"self": {"href": "https://publications.scilifelab.se/publication/598feb16626f43cdb791a3f07b3a488b.json"}, "display": {"href": "https://publications.scilifelab.se/publication/598feb16626f43cdb791a3f07b3a488b"}}, "title": "Molecular view of ER membrane remodeling by the Sec61/TRAP translocon.", "authors": [{"family": "Karki", "given": "Sudeep", "initials": "S", "orcid": "0000-0003-3851-1204", "researcher": {"href": "https://publications.scilifelab.se/researcher/2872667c8b6f400bb2373e19ef70e629.json"}}, {"family": "Javanainen", "given": "Matti", "initials": "M", "orcid": "0000-0003-4858-364X", "researcher": {"href": "https://publications.scilifelab.se/researcher/9d89f643000047efb67c8b68340601b9.json"}}, {"family": "Rehan", "given": "Shahid", "initials": "S", "orcid": "0000-0003-1329-8056", "researcher": {"href": "https://publications.scilifelab.se/researcher/5fe8a426af3d4750906f849a48526806.json"}}, {"family": "Tranter", "given": "Dale", "initials": "D"}, {"family": "Kellosalo", "given": "Juho", "initials": "J"}, {"family": "Huiskonen", "given": "Juha", "initials": "J", "orcid": "0000-0002-0348-7323", "researcher": {"href": "https://publications.scilifelab.se/researcher/c858a2e60971462f9e53653320c9eb0f.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Paavilainen", "given": "Ville", "initials": "V", "orcid": "0000-0002-3160-7767", "researcher": {"href": "https://publications.scilifelab.se/researcher/f76359e8b92b4b53af80c36d064a1a42.json"}}], "type": "journal article", "published": "2023-11-20", "journal": {"title": "EMBO Rep.", "issn": "1469-3178", "pages": "e57910", "issn-l": "1469-221X"}, "abstract": "Protein translocation across the endoplasmic reticulum (ER) membrane is an essential step during protein entry into the secretory pathway. The conserved Sec61 protein-conducting channel facilitates polypeptide translocation and coordinates cotranslational polypeptide-processing events. In cells, the majority of Sec61 is stably associated with a heterotetrameric membrane protein complex, the translocon-associated protein complex (TRAP), yet the mechanism by which TRAP assists in polypeptide translocation remains unknown. Here, we present the structure of the core Sec61/TRAP complex bound to a mammalian ribosome by cryogenic electron microscopy (cryo-EM). Ribosome interactions anchor the Sec61/TRAP complex in a conformation that renders the ER membrane locally thinner by significantly curving its lumenal leaflet. We propose that TRAP stabilizes the ribosome exit tunnel to assist nascent polypeptide insertion through Sec61 and provides a ratcheting mechanism into the ER lumen mediated by direct polypeptide interactions.", "doi": "10.15252/embr.202357910", "pmid": "37983950", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "PDB", "key": "8BF9"}], "notes": [], "created": "2023-12-01T13:22:27.535Z", "modified": "2023-12-01T13:22:27.636Z"}, {"entity": "publication", "iuid": "795e2038e25f4e18a0ad1d522a57a3b3", "links": {"self": {"href": "https://publications.scilifelab.se/publication/795e2038e25f4e18a0ad1d522a57a3b3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/795e2038e25f4e18a0ad1d522a57a3b3"}}, "title": "Reduced binding of apoE4 to complement factor H promotes amyloid-\u03b2 oligomerization and neuroinflammation.", "authors": [{"family": "Chernyaeva", "given": "Larisa", "initials": "L"}, {"family": "Ratti", "given": "Giorgio", "initials": "G", "orcid": "0000-0002-9938-2752", "researcher": {"href": "https://publications.scilifelab.se/researcher/fa9eca4386e3401690b213a563333708.json"}}, {"family": "Teiril\u00e4", "given": "Laura", "initials": "L"}, {"family": "Fudo", "given": "Satoshi", "initials": "S", "orcid": "0000-0001-9925-5131", "researcher": {"href": "https://publications.scilifelab.se/researcher/759009323fc946d4b76ca557460b14fe.json"}}, {"family": "Rankka", "given": "Uni", "initials": "U", "orcid": "0009-0006-0061-627X", "researcher": {"href": "https://publications.scilifelab.se/researcher/8876a5db4893489bb555826afc9b437e.json"}}, {"family": "Pelkonen", "given": "Anssi", "initials": "A"}, {"family": "Korhonen", "given": "Paula", "initials": "P", "orcid": "0000-0001-5856-1474", "researcher": {"href": "https://publications.scilifelab.se/researcher/3f477ee490c54644bb230db40930c331.json"}}, {"family": "Leskinen", "given": "Katarzyna", "initials": "K"}, {"family": "Keskitalo", "given": "Salla", "initials": "S", "orcid": "0000-0001-5555-1975", "researcher": {"href": "https://publications.scilifelab.se/researcher/6fcfe7acf8b34414af414dfe59619a78.json"}}, {"family": "Salokas", "given": "Kari", "initials": "K", "orcid": "0000-0002-4471-6698", "researcher": {"href": "https://publications.scilifelab.se/researcher/158142e4fff84a8e98e965eb73f574fa.json"}}, {"family": "Gkolfinopoulou", "given": "Christina", "initials": "C"}, {"family": "Crompton", "given": "Katrina E", "initials": "KE"}, {"family": "Javanainen", "given": "Matti", "initials": "M", "orcid": "0000-0003-4858-364X", "researcher": {"href": "https://publications.scilifelab.se/researcher/9d89f643000047efb67c8b68340601b9.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Varjosalo", "given": "Markku", "initials": "M", "orcid": "0000-0002-1340-9732", "researcher": {"href": "https://publications.scilifelab.se/researcher/631a0a4964d747399c0b1781e546f0ab.json"}}, {"family": "Malm", "given": "Tarja", "initials": "T"}, {"family": "Leinonen", "given": "Ville", "initials": "V", "orcid": "0000-0002-4282-4687", "researcher": {"href": "https://publications.scilifelab.se/researcher/0a0cda2550f84aa98a6492c9353900db.json"}}, {"family": "Chroni", "given": "Angeliki", "initials": "A", "orcid": "0000-0003-3107-1189", "researcher": {"href": "https://publications.scilifelab.se/researcher/c5fb9abe7c434935a7960d8d2ca06383.json"}}, {"family": "Saavalainen", "given": "P\u00e4ivi", "initials": "P"}, {"family": "Meri", "given": "Seppo", "initials": "S"}, {"family": "Kajander", "given": "Tommi", "initials": "T", "orcid": "0000-0002-5094-227X", "researcher": {"href": "https://publications.scilifelab.se/researcher/87663a9c5a1d4a3a8b8ecd9a7786da41.json"}}, {"family": "Wollman", "given": "Adam Jm", "initials": "AJ", "orcid": "0000-0002-5501-8131", "researcher": {"href": "https://publications.scilifelab.se/researcher/ab952da1fa7b4bf1943dca21d96ffd39.json"}}, {"family": "Nissil\u00e4", "given": "Eija", "initials": "E", "orcid": "0000-0002-8089-1266", "researcher": {"href": "https://publications.scilifelab.se/researcher/da4f5c3ecd1c4b39b1e7daa0b38741e7.json"}}, {"family": "Haapasalo", "given": "Karita", "initials": "K", "orcid": "0000-0002-9619-625X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3b20237314dd44a18c5d66ce460570ee.json"}}], "type": "journal article", "published": "2023-05-08", "journal": {"title": "EMBO Rep.", "issn": "1469-3178", "pages": "e56467", "issn-l": "1469-221X"}, "abstract": "The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters A\u03b21-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of A\u03b21-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/A\u03b21-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce A\u03b21-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on A\u03b2 plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.", "doi": "10.15252/embr.202256467", "pmid": "37155564", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "GEO", "key": "GSE193513"}], "notes": [], "created": "2023-05-31T19:05:44.032Z", "modified": "2023-05-31T19:05:44.613Z"}, {"entity": "publication", "iuid": "e006d97516fc46078c223b8ef61e1495", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e006d97516fc46078c223b8ef61e1495.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e006d97516fc46078c223b8ef61e1495"}}, "title": "A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function.", "authors": [{"family": "Bahnan", "given": "Wael", "initials": "W"}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Khakzad", "given": "Hamed", "initials": "H"}, {"family": "Kumra Ahnlide", "given": "Vibha", "initials": "V"}, {"family": "de Neergaard", "given": "Therese", "initials": "T", "orcid": "0000-0002-6969-0375", "researcher": {"href": "https://publications.scilifelab.se/researcher/6a0741a1bb054897af22536a29071291.json"}}, {"family": "Wrighton", "given": "Sebastian", "initials": "S", "orcid": "0000-0002-3378-7925", "researcher": {"href": "https://publications.scilifelab.se/researcher/0b5821cc01364325a4b9fe177e7f6e33.json"}}, {"family": "Andr\u00e9", "given": "Oscar", "initials": "O"}, {"family": "Bratanis", "given": "Eleni", "initials": "E", "orcid": "0000-0002-0636-6658", "researcher": {"href": "https://publications.scilifelab.se/researcher/c935953f81fc4d8eb6a9b9ddb7774c1b.json"}}, {"family": "Tang", "given": "Di", "initials": "D", "orcid": "0000-0001-6323-9375", "researcher": {"href": "https://publications.scilifelab.se/researcher/e2a27467c4094d9f8d8f8402efa333f4.json"}}, {"family": "Hellmark", "given": "Thomas", "initials": "T", "orcid": "0000-0002-2952-1155", "researcher": {"href": "https://publications.scilifelab.se/researcher/13f4a44a5f0d4c69a7eb1da54a15a677.json"}}, {"family": "Bj\u00f6rck", "given": "Lars", "initials": "L", "orcid": "0000-0003-1686-3161", "researcher": {"href": "https://publications.scilifelab.se/researcher/a37198ab5bfa4dcebc6f75e2b778107d.json"}}, {"family": "Shannon", "given": "Oonagh", "initials": "O"}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L"}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}, {"family": "Nordenfelt", "given": "Pontus", "initials": "P", "orcid": "0000-0002-9481-9951", "researcher": {"href": "https://publications.scilifelab.se/researcher/7aa3418ab23a4ec48c037d6d6ddea5b5.json"}}], "type": "journal article", "published": "2023-02-08", "journal": {"title": "EMBO Mol Med", "issn": "1757-4684", "volume": "15", "issue": "2", "pages": "e16208", "issn-l": "1757-4676"}, "abstract": "Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.", "doi": "10.15252/emmm.202216208", "pmid": "36507602", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC9906385"}], "notes": [], "created": "2023-05-31T19:04:08.995Z", "modified": "2023-05-31T19:04:09.267Z"}, {"entity": "publication", "iuid": "32532dfcd911424f93ddea636563394f", "links": {"self": {"href": "https://publications.scilifelab.se/publication/32532dfcd911424f93ddea636563394f.json"}, "display": {"href": "https://publications.scilifelab.se/publication/32532dfcd911424f93ddea636563394f"}}, "title": "Snapshots of actin and tubulin folding inside the TRiC chaperonin.", "authors": [{"family": "Kelly", "given": "John J", "initials": "JJ"}, {"family": "Tranter", "given": "Dale", "initials": "D"}, {"family": "Pardon", "given": "Els", "initials": "E", "orcid": "0000-0002-2466-0172", "researcher": {"href": "https://publications.scilifelab.se/researcher/375719a54c844150a4d5cb2b4f3ebb57.json"}}, {"family": "Chi", "given": "Gamma", "initials": "G"}, {"family": "Kramer", "given": "Holger", "initials": "H", "orcid": "0000-0002-6400-0945", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf9fb27444604e999fe8815be9eb336a.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Knee", "given": "Kelly M", "initials": "KM"}, {"family": "Janz", "given": "Jay M", "initials": "JM"}, {"family": "Steyaert", "given": "Jan", "initials": "J", "orcid": "0000-0002-3825-874X", "researcher": {"href": "https://publications.scilifelab.se/researcher/2a13eb5511e1448fb982b5bd1bb1d6f1.json"}}, {"family": "Bulawa", "given": "Christine", "initials": "C"}, {"family": "Paavilainen", "given": "Ville O", "initials": "VO", "orcid": "0000-0002-3160-7767", "researcher": {"href": "https://publications.scilifelab.se/researcher/f76359e8b92b4b53af80c36d064a1a42.json"}}, {"family": "Huiskonen", "given": "Juha T", "initials": "JT", "orcid": "0000-0002-0348-7323", "researcher": {"href": "https://publications.scilifelab.se/researcher/c858a2e60971462f9e53653320c9eb0f.json"}}, {"family": "Yue", "given": "Wyatt W", "initials": "WW", "orcid": "0000-0001-6959-6007", "researcher": {"href": "https://publications.scilifelab.se/researcher/5be92e7076054a009efe9d23f78b5a48.json"}}], "type": "journal article", "published": "2022-04-21", "journal": {"title": "Nat. Struct. Mol. Biol.", "issn": "1545-9985", "issn-l": "1545-9985"}, "abstract": "The integrity of a cell's proteome depends on correct folding of polypeptides by chaperonins. The chaperonin TCP-1 ring complex (TRiC) acts as obligate folder for >10% of cytosolic proteins, including he cytoskeletal proteins actin and tubulin. Although its architecture and how it recognizes folding substrates are emerging from structural studies, the subsequent fate of substrates inside the TRiC chamber is not defined. We trapped endogenous human TRiC with substrates (actin, tubulin) and cochaperone (PhLP2A) at different folding stages, for structure determination by cryo-EM. The already-folded regions of client proteins are anchored at the chamber wall, positioning unstructured regions toward the central space to achieve their native fold. Substrates engage with different sections of the chamber during the folding cycle, coupled to TRiC open-and-close transitions. Further, the cochaperone PhLP2A modulates folding, acting as a molecular strut between substrate and TRiC chamber. Our structural snapshots piece together an emerging model of client protein folding within TRiC.", "doi": "10.1038/s41594-022-00755-1", "pmid": "35449234", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41594-022-00755-1"}], "notes": [], "created": "2022-04-27T14:22:02.454Z", "modified": "2022-04-27T14:22:02.677Z"}, {"entity": "publication", "iuid": "58bd18b8aa7c4321abc5d8460a21059b", "links": {"self": {"href": "https://publications.scilifelab.se/publication/58bd18b8aa7c4321abc5d8460a21059b.json"}, "display": {"href": "https://publications.scilifelab.se/publication/58bd18b8aa7c4321abc5d8460a21059b"}}, "title": "The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms.", "authors": [{"family": "Hasan", "given": "Mahmudul", "initials": "M", "orcid": "0000-0002-1767-6440", "researcher": {"href": "https://publications.scilifelab.se/researcher/67859983152248efb9f5a0461b168273.json"}}, {"family": "Khakzad", "given": "Hamed", "initials": "H", "orcid": "0000-0002-8556-0650", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7b030c1452c4dc9b430deffdf493e6f.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Sundin", "given": "Anders", "initials": "A", "orcid": "0000-0001-6615-2419", "researcher": {"href": "https://publications.scilifelab.se/researcher/b03a78e59f0845c5b68b372f2709dbf0.json"}}, {"family": "Unge", "given": "Johan", "initials": "J", "orcid": "0000-0002-1077-8137", "researcher": {"href": "https://publications.scilifelab.se/researcher/a3aa8d0b4eaf489b8b35e825bb522ca0.json"}}, {"family": "Mueller", "given": "Uwe", "initials": "U", "orcid": "0000-0002-7139-0718", "researcher": {"href": "https://publications.scilifelab.se/researcher/0dec0ec0f53448d19f40b384e727daff.json"}}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}, {"family": "Westergren-Thorsson", "given": "Gunilla", "initials": "G", "orcid": "0000-0001-5327-8805", "researcher": {"href": "https://publications.scilifelab.se/researcher/08bbfee41c5545779fa88211baeeb216.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}, {"family": "Ellervik", "given": "Ulf", "initials": "U", "orcid": "0000-0001-5287-0137", "researcher": {"href": "https://publications.scilifelab.se/researcher/079345b11c884e25ae5f968b70eb9d13.json"}}, {"family": "Malmstr\u00f6m", "given": "Anders", "initials": "A", "orcid": "0000-0002-6691-146X", "researcher": {"href": "https://publications.scilifelab.se/researcher/2c756d46971f4670abdb5faafb10ad56.json"}}, {"family": "Tykesson", "given": "Emil", "initials": "E", "orcid": "0000-0002-0511-9831", "researcher": {"href": "https://publications.scilifelab.se/researcher/bd615245d50b47639f38f55fbf3f4fe3.json"}}], "type": "journal article", "published": "2021-02-07", "journal": {"title": "Chem. Sci.", "issn": "2041-6520", "volume": "12", "issue": "5", "pages": "1869-1885", "issn-l": null}, "abstract": "Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 \u00c5 resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.", "doi": "10.1039/d0sc05971d", "pmid": "33815739", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pii", "key": "d0sc05971d"}, {"db": "pmc", "key": "PMC8006597"}], "notes": [], "created": "2021-12-03T12:29:01.165Z", "modified": "2021-12-03T12:29:01.545Z"}, {"entity": "publication", "iuid": "03a9bb0f8fa14a829220610e1ac822c4", "links": {"self": {"href": "https://publications.scilifelab.se/publication/03a9bb0f8fa14a829220610e1ac822c4.json"}, "display": {"href": "https://publications.scilifelab.se/publication/03a9bb0f8fa14a829220610e1ac822c4"}}, "title": "Structural determination of Streptococcus pyogenes M1 protein interactions with human immunoglobulin G using integrative structural biology.", "authors": [{"family": "Khakzad", "given": "Hamed", "initials": "H", "orcid": "0000-0002-8556-0650", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7b030c1452c4dc9b430deffdf493e6f.json"}}, {"family": "Happonen", "given": "Lotta", "initials": "L", "orcid": "0000-0002-5922-4549", "researcher": {"href": "https://publications.scilifelab.se/researcher/a7af0a6faf6a48e7937a644be472edbe.json"}}, {"family": "Karami", "given": "Yasaman", "initials": "Y", "orcid": "0000-0001-8413-2665", "researcher": {"href": "https://publications.scilifelab.se/researcher/a71f08b3f3794e66b7adae400c14f142.json"}}, {"family": "Chowdhury", "given": "Sounak", "initials": "S"}, {"family": "Bergdahl", "given": "Gizem Ert\u00fcrk", "initials": "GE", "orcid": "0000-0001-9719-6609", "researcher": {"href": "https://publications.scilifelab.se/researcher/f3671f82049b4e8e96fd45b0e0351642.json"}}, {"family": "Nilges", "given": "Michael", "initials": "M", "orcid": "0000-0002-1451-8092", "researcher": {"href": "https://publications.scilifelab.se/researcher/ebfd5336137d4eaabde8f4f9baed470a.json"}}, {"family": "Tran Van Nhieu", "given": "Guy", "initials": "G"}, {"family": "Malmstr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0002-2889-7169", "researcher": {"href": "https://publications.scilifelab.se/researcher/ad3c999da10c41e4a3afda2718815083.json"}}, {"family": "Malmstr\u00f6m", "given": "Lars", "initials": "L", "orcid": "0000-0001-9885-9312", "researcher": {"href": "https://publications.scilifelab.se/researcher/42e99f34fb854beb8d810b05fe941057.json"}}], "type": "journal article", "published": "2021-01-00", "journal": {"title": "PLoS Comput. Biol.", "issn": "1553-7358", "volume": "17", "issue": "1", "pages": "e1008169", "issn-l": "1553-734X"}, "abstract": "Streptococcus pyogenes (Group A streptococcus; GAS) is an important human pathogen responsible for mild to severe, life-threatening infections. GAS expresses a wide range of virulence factors, including the M family proteins. The M proteins allow the bacteria to evade parts of the human immune defenses by triggering the formation of a dense coat of plasma proteins surrounding the bacteria, including IgGs. However, the molecular level details of the M1-IgG interaction have remained unclear. Here, we characterized the structure and dynamics of this interaction interface in human plasma on the surface of live bacteria using integrative structural biology, combining cross-linking mass spectrometry and molecular dynamics (MD) simulations. We show that the primary interaction is formed between the S-domain of M1 and the conserved IgG Fc-domain. In addition, we show evidence for a so far uncharacterized interaction between the A-domain and the IgG Fc-domain. Both these interactions mimic the protein G-IgG interface of group C and G streptococcus. These findings underline a conserved scavenging mechanism used by GAS surface proteins that block the IgG-receptor (Fc\u03b3R) to inhibit phagocytic killing. We additionally show that we can capture Fab-bound IgGs in a complex background and identify XLs between the constant region of the Fab-domain and certain regions of the M1 protein engaged in the Fab-mediated binding. Our results elucidate the M1-IgG interaction network involved in inhibition of phagocytosis and reveal important M1 peptides that can be further investigated as future vaccine targets.", "doi": "10.1371/journal.pcbi.1008169", "pmid": "33411763", "labels": {"Structural Proteomics": "Collaborative"}, "xrefs": [{"db": "pii", "key": "PCOMPBIOL-D-20-01263"}, {"db": "pmc", "key": "PMC7817036"}], "notes": [], "created": "2021-12-03T12:29:48.339Z", "modified": "2021-12-03T12:29:48.505Z"}]}