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Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23512-23517. doi: 10.1073/pnas.1905455116. Epub 2019 Nov 5.

Pat1 activates late steps in mRNA decay by multiple mechanisms.

Author information

1
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA 94158.
2
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 jdgross@cgl.ucsf.edu.

Abstract

Pat1 is a hub for mRNA metabolism, acting in pre-mRNA splicing, translation repression, and mRNA decay. A critical step in all 5'-3' mRNA decay pathways is removal of the 5' cap structure, which precedes and permits digestion of the RNA body by conserved exonucleases. During bulk 5'-3' decay, the Pat1/Lsm1-7 complex engages mRNA at the 3' end and promotes hydrolysis of the cap structure by Dcp1/Dcp2 at the 5' end through an unknown mechanism. We reconstitute Pat1 with 5' and 3' decay factors and show how it activates multiple steps in late mRNA decay. First, we find that Pat1 stabilizes binding of the Lsm1-7 complex to RNA using two conserved short-linear interaction motifs. Second, Pat1 directly activates decapping by binding elements in the disordered C-terminal extension of Dcp2, alleviating autoinhibition and promoting substrate binding. Our results uncover the molecular mechanism of how separate domains of Pat1 coordinate the assembly and activation of a decapping messenger ribonucleoprotein (mRNP) that promotes 5'-3' mRNA degradation.

KEYWORDS:

Dcp2; Pat1; decapping; mRNA decay; short-linear interaction motifs

PMID:
31690658
PMCID:
PMC6876151
[Available on 2020-05-05]
DOI:
10.1073/pnas.1905455116

Conflict of interest statement

The authors declare no competing interest.

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