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An asymmetric PAN3 dimer recruits a single PAN2 exonuclease to mediate mRNA deadenylation and decay.

Jonas S, Christie M, Peter D, Bhandari D, Loh B, Huntzinger E, Weichenrieder O, Izaurralde E
Nat Struct Mol Biol 21 599-608 (2014)
Related entries: 4czv, 4czw, 4czy, 4d0k

Cited: 30 times
EuropePMC logo PMID: 24880343

Abstract

The PAN2-PAN3 complex functions in general and microRNA-mediated mRNA deadenylation. However, mechanistic insight into PAN2 and its complex with the asymmetric PAN3 dimer is lacking. Here, we describe crystal structures that show that Neurospora crassa PAN2 comprises two independent structural units: a C-terminal catalytic unit and an N-terminal assembly unit that engages in a bipartite interaction with PAN3 dimers. The catalytic unit contains the exonuclease domain in an intimate complex with a potentially modulatory ubiquitin-protease-like domain. The assembly unit contains a WD40 propeller connected to an adaptable linker. The propeller contacts the PAN3 C-terminal domain, whereas the linker reinforces the asymmetry of the PAN3 dimer and prevents the recruitment of a second PAN2 molecule. Functional data indicate an essential role for PAN3 in coordinating PAN2-mediated deadenylation with subsequent steps in mRNA decay, which lead to complete mRNA degradation.

Reviews citing this publication (11)

  1. Towards a molecular understanding of microRNA-mediated gene silencing. Jonas S, Izaurralde E. Nat Rev Genet 16 421-433 (2015)
  2. The Functions of MicroRNAs: mRNA Decay and Translational Repression. Iwakawa HO, Tomari Y. Trends Cell Biol 25 651-665 (2015)
  3. Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Passmore LA, Coller J. Nat Rev Mol Cell Biol 23 93-106 (2022)
  4. Structural Foundations of RNA Silencing by Argonaute. Sheu-Gruttadauria J, MacRae IJ. J Mol Biol 429 2619-2639 (2017)
  5. Structural and molecular mechanisms for the control of eukaryotic 5'-3' mRNA decay. Mugridge JS, Coller J, Gross JD. Nat Struct Mol Biol 25 1077-1085 (2018)
  6. Prospects for pharmacological targeting of pseudokinases. Kung JE, Jura N. Nat Rev Drug Discov 18 501-526 (2019)
  7. The Interplay between the RNA Decay and Translation Machinery in Eukaryotes. Heck AM, Wilusz J. Cold Spring Harb Perspect Biol 10 a032839 (2018)
  8. There's more to death than life: Noncatalytic functions in kinase and pseudokinase signaling. Mace PD, Murphy JM. J Biol Chem 296 100705 (2021)
  9. Nucleotide-binding mechanisms in pseudokinases. Hammarén HM, Virtanen AT, Silvennoinen O. Biosci Rep 36 e00282 (2015)
  10. Regulation of cytoplasmic RNA stability: Lessons from Drosophila. Towler BP, Newbury SF. Wiley Interdiscip Rev RNA 9 e1499 (2018)
  11. Structure and function of molecular machines involved in deadenylation-dependent 5'-3' mRNA degradation. Zhao Q, Pavanello L, Bartlam M, Winkler GS. Front Genet 14 1233842 (2023)

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