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Structural Basis for Target-Directed MicroRNA Degradation

48 Pages Posted: 26 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Jessica Sheu-Gruttadauria

Jessica Sheu-Gruttadauria

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Paulina Pawlica

Yale University - Department of Molecular Biophysics and Biochemistry

Shannon M. Klum

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Sonia Wang

Yale University - Department of Molecular Biophysics and Biochemistry

Therese A. Yario

Yale University - Department of Molecular Biophysics and Biochemistry

Nicole T. Schirle Oakdale

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Joan A. Steitz

Yale University - Department of Molecular Biophysics and Biochemistry

Ian J. MacRae

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

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Abstract

MicroRNAs (miRNAs) broadly regulate gene expression through association with Argonaute (Ago), which also protects miRNAs from degradation. However, miRNA stability is known to vary and be regulated by poorly understood mechanisms. A major emerging process, termed target-directed miRNA degradation (TDMD), employs specialized target RNAs to selectively bind to miRNAs and induce their decay. Here, we report structures of human Ago2 (hAgo2) bound to miRNAs and TDMD-inducing targets. miRNA and target form a bipartite duplex connected by an unpaired flexible linker. hAgo2 cannot physically accommodate the RNA, causing the duplex to bend at the linker and display the miRNA 3'-end for enzymatic attack. Altering 3'-end display by changing linker flexibility, 3'-end complementarity, or mutationally inducing 3'-end release impacts TDMD efficiency leading to production of distinct 3'-miRNA isoforms in cells. These results uncover the mechanism driving TDMD and reveal 3'-end display as a key determinant regulating miRNA activity via 3'-remodeling and/or degradation.

Suggested Citation

Sheu-Gruttadauria, Jessica and Pawlica, Paulina and Klum, Shannon M. and Wang, Sonia and Yario, Therese A. and Oakdale, Nicole T. Schirle and Steitz, Joan A. and MacRae, Ian J., Structural Basis for Target-Directed MicroRNA Degradation (January 24, 2019). Available at SSRN: https://ssrn.com/abstract=3318944 or http://dx.doi.org/10.2139/ssrn.3318944
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jessica Sheu-Gruttadauria

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Paulina Pawlica

Yale University - Department of Molecular Biophysics and Biochemistry

New Haven, CT 06520
United States

Shannon M. Klum

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Sonia Wang

Yale University - Department of Molecular Biophysics and Biochemistry

New Haven, CT 06520
United States

Therese A. Yario

Yale University - Department of Molecular Biophysics and Biochemistry

New Haven, CT 06520
United States

Nicole T. Schirle Oakdale

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Joan A. Steitz (Contact Author)

Yale University - Department of Molecular Biophysics and Biochemistry ( email )

New Haven, CT 06520
United States

Ian J. MacRae

The Scripps Research Institute - Department of Integrative Structural and Computational Biology ( email )

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

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