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To accomplish this, bacterial AB toxins evolved a multidomain structure organized into either a single polypeptide chain or non-covalently associated polypeptide chains. The prototypical short-trip single-chain toxin is characterized by a receptor-binding domain that confers cellular specificity and a translocation domain responsible for pore formation whereby the catalytic domain translocates to the cytosol in an endosomal acidification-dependent way. In this work, the determination of the three-dimensional structure of AIP56 shows that, instead of a two-domain organization suggested by previous studies, AIP56 has three-domains: a non-LEE encoded effector C (NleC)-like catalytic domain associated with a small middle domain that contains the linker-peptide, followed by the receptor-binding domain. In contrast to prototypical single-chain AB toxins, AIP56 does not comprise a typical structurally complex translocation domain; instead, the elements involved in translocation are scattered across its domains. Thus, the catalytic domain contains a helical hairpin that serves as a molecular switch for triggering the conformational changes necessary for membrane insertion only upon endosomal acidification, whereas the middle and receptor-binding domains are required for pore formation.<\/jats:p>","DOI":"10.1038\/s41467-023-43054-z","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T16:41:07Z","timestamp":1700152867000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unconventional structure and mechanisms for membrane interaction and translocation of the NF-\u03baB-targeting toxin AIP56"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7329-8993","authenticated-orcid":false,"given":"Johnny","family":"Lisboa","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5514-4544","authenticated-orcid":false,"given":"Cassilda","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"Rute D.","family":"Pinto","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4335-0724","authenticated-orcid":false,"given":"In\u00eas S.","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Liliana M. 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