PT  - JOURNAL ARTICLE
AU  - Jana Kubikova
AU  - Gabriele Ubartaite
AU  - Jutta Metz
AU  - Mandy Jeske
TI  - Structural basis for binding of Smaug to the GPCR Smoothened and to the germline inducer Oskar
AID  - 10.1101/2023.02.19.529116
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.02.19.529116
4099  - http://biorxiv.org/content/early/2023/02/19/2023.02.19.529116.short
4100  - http://biorxiv.org/content/early/2023/02/19/2023.02.19.529116.full
AB  - Drosophila Smaug and its orthologs comprise a family of mRNA repressor proteins that exhibit various functions during animal development. Smaug proteins contain a characteristic RNA-binding sterile-a motif (SAM) domain and a conserved but uncharacterized N-terminal domain (NTD). Here, we resolved the crystal structure of the NTD of the human SAM domain-containing protein 4A (SAMD4A, a.k.a. Smaug1) to 2.0 Å resolution, which revealed its composition of a homodimerization D-subdomain and a subdomain with similarity to a PHAT domain. Furthermore, we show that Drosophila Smaug directly interacts with the Drosophila germline inducer Oskar and with the Hedgehog signaling transducer Smoothened through its D-PHAT domain. We determined the crystal structure of the D-PHAT domain of Smaug in complex with a Smoothened a-helical peptide to 1.61 Å resolution. The peptide binds within a groove that is formed by both the D- and PHAT subdomains. Structural modeling supported by experimental data suggested that an a-helix within the disordered region of Oskar binds to the D-PHAT domain in a mode similar to Smoothened. Together, our data uncover the N-terminal D-PHAT domain of Smaug as peptide-binding domain.Competing Interest StatementThe authors have declared no competing interest.