{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T16:25:00Z","timestamp":1793377500515,"version":"4.5.0"},"reference-count":37,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,23]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryogenic electron microscopy (cryo-EM) structure of a native, human plasma\u2013derived FXIII-A2B2 complex at 2.4 \u00c5 resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the 2 subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudosymmetric heterotetramer of 2 FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a \u201ccrown\u201d-like assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit, and Sushi domain 2 with the symmetry related A\u2032 subunit, and vice versa. We also report 4 novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024025369","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T19:02:40Z","timestamp":1729796560000},"page":"438-449","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":14,"title":["Cryo-EM structure of the human native plasma coagulation factor XIII complex"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1652-0307","authenticated-orcid":false,"given":"Sneha","family":"Singh","sequence":"first","affiliation":[{"name":"1Arijit Biswas Laboratory, Institute for Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Hagelueken","sequence":"additional","affiliation":[{"name":"2Institute of Structural Biology, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8841-3851","authenticated-orcid":false,"given":"Deniz","family":"Ugurlar","sequence":"additional","affiliation":[{"name":"3Materials and Structural Analysis, ThermoFisher Scientific, Eindhoven, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samhitha Urs","family":"Ramaraje Urs","sequence":"additional","affiliation":[{"name":"1Arijit Biswas Laboratory, Institute for Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Sharma","sequence":"additional","affiliation":[{"name":"4Department of Hematology, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoranjan","family":"Mahapatra","sequence":"additional","affiliation":[{"name":"4Department of Hematology, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2043-5795","authenticated-orcid":false,"given":"Friedel","family":"Drepper","sequence":"additional","affiliation":[{"name":"5Institute of Biology II, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-7334","authenticated-orcid":false,"given":"Diana","family":"Imhof","sequence":"additional","affiliation":[{"name":"6Pharmaceutical Institute, University of Bonn, Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-2242","authenticated-orcid":false,"given":"Pitter 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