Structural insights into inherited anemia CDA-I: disease-associated mutations disrupt CDIN1-Codanin1 complex

Abstract

AbstractCongenital dyserythropoietic anemia type I (CDA-I) is a rare hereditary disease characterized by ineffective erythropoiesis and associated mutations in two proteins – Codanin1 and CDIN1. The primary role of Codanin1 is nucleosome assembly regulation through interaction with ASF1. The role of recently discovered CDIN1 remains unknown, but CDIN1 has been known to interact directly with the C-terminus of Codanin1. Despite the critical role of identified mutations in Codanin1 and CDIN1, the effects of CDA-I-related mutations at the molecular level have not been elucidated.Here, we reconstruct the structural envelopes of CDIN1 and Codanin1, determine stoichiometry, define essential interacting regions, and quantify mutual affinity. We demonstrate that the anemia-associated mutations disturb CDIN1 and Codanin1 binding. Our findings present new insights into the structure of Codanin1 and CDIN1 and the functional effects of disease-associated mutations as the next step in unraveling the molecular etiology of CDA-I disease.Graphical AbstractHighlightsFull-length CDIN1 preferentially forms dimers, Codanin1CtermmonomersCDIN1 binds Codanin1Ctermin equimolar ratio with nanomolar affinityDetermined interacting regions of CDIN1 and Codanin1Ctermcontain mutations associated with CDA-I diseaseCDA-I-related mutations disrupt the binding of CDIN1 and Codanin1Cterm