Inhibition of FAM46/TENT5 activity by BCCIP? adopting a unique fold

The FAM46 (also known as TENT5) proteins are noncanonical poly(A) polymerases (PAPs) implicated in regulat-ing RNA stability. The regulatory mechanisms of FAM46 are poorly understood. Here, we report that the nuclear protein BCCIP alpha, but not the alternatively spliced isoform BCCIPII, binds FAM46 and inhibits their PAP activity. Unexpectedly, our structures of the FAM46A/BCCIP alpha and FAM46C/BCCIP alpha complexes show that, despite sharing most of the sequence and differing only at the C-terminal portion, BCCIP alpha adopts a unique structure completely different from BCCIPII. The distinct C-terminal segment of BCCIP alpha supports the adoption of the unique fold but does not directly interact with FAM46. The II sheets in BCCIP alpha and FAM46 pack side by side to form an extended II sheet. A helix-loop-helix segment in BCCIP alpha inserts into the active site cleft of FAM46, thereby inhibiting the PAP activity. Our results together show that the unique fold of BCCIP alpha underlies its interaction with and func-tional regulation of FAM46.

Automated summary

This study reveals that the nuclear protein BCCIP alpha binds to FAM46 and inhibits its PAP activity, thus affecting RNA stability. Structural analysis shows that BCCIP alpha, despite sharing most of the sequence with BCCIPII, adopts a unique fold completely different from BCCIPII. The unique fold of BCCIP alpha underlies its interaction with and functional regulation of FAM46.