RT Journal Article SR Electronic T1 Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26 JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201418 DO 10.26508/lsa.202201418 VO 5 IS 8 A1 Salerno-Kochan, Anna A1 Horn, Andreas A1 Ghosh, Pritha A1 Nithin, Chandran A1 Kościelniak, Anna A1 Meindl, Andreas A1 Strauss, Daniela A1 Krutyhołowa, Rościsław A1 Rossbach, Oliver A1 Bujnicki, Janusz M A1 Gaik, Monika A1 Medenbach, Jan A1 Glatt, Sebastian YR 2022 UL https://www.life-science-alliance.org/content/5/8/e202201418.abstract AB The TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes, and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression; however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins.