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Vesiculin, a naturally occurring\n                    <jats:italic>des<\/jats:italic>\n                    [37\u201340]IGF2 isoform, represents a unique probe for dissecting these interactions. Here, we combine chemical synthesis, receptor\u2010binding assays, phosphorylation studies, and molecular dynamics simulations to characterize vesiculin and compare it with wild\u2010type IGF2. Vesiculin consistently displayed a reduced affinity for the majority of binding partners, with the most pronounced loss observed for IGF2R and its isolated domain 11 (D11). Computational analyses revealed that this reduction originates from the destabilization of the IGF2 C\u2010domain, which in wild\u2010type IGF2 forms cooperative contacts with IGF2R domains D6 and D8. Deletion of Arg37\u2010Arg40 abolishes these interactions and enforces ineffective compensatory contacts. For the insulin receptor, the loss of these residues disrupts stabilizing electrostatic contacts with the \u03b1\u2010CT and L2 domains. In contrast, IGF1R binding is only modestly affected, and vesiculin shows a markedly diminished affinity for IGFBP3, raising questions about its bioactivity. Together, these findings redefine the IGF2\u2013IGF2R binding interface and highlight the IGF2 C\u2010domain as a central determinant of receptor specificity across the insulin\u2013IGF system, providing a framework for designing IGF2 analogs.\n                  <\/jats:p>","DOI":"10.1002\/pro.70606","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:35:01Z","timestamp":1777718101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vesiculin reveals the role of the\n                    <scp>IGF2<\/scp>\n                    C\u2010domain in receptor specificity within the insulin\u2013\n                    <scp>IGF<\/scp>\n                    system"],"prefix":"10.1002","volume":"35","author":[{"given":"Karol\u00edna","family":"Mrz\u00edlkov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague 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