PMID- 21552258
OWN - NLM
STAT- MEDLINE
DCOM- 20110620
LR  - 20230106
IS  - 1545-9985 (Electronic)
IS  - 1545-9993 (Print)
IS  - 1545-9985 (Linking)
VI  - 18
IP  - 6
DP  - 2011 Jun
TI  - Structure of C3PO and mechanism of human RISC activation.
PG  - 650-7
LID - 10.1038/nsmb.2032 [doi]
AB  - Assembly of the RNA-induced silencing complex (RISC) consists of loading duplex 
      (guide-passenger) siRNA onto Argonaute (Ago2) and removing the passenger strand. 
      Ago2 contributes critically to RISC activation by nicking the passenger strand. 
      Here we reconstituted duplex siRNA-initiated RISC activity using recombinant 
      human Ago2 (hAgo2) and C3PO, indicating that C3PO has a critical role in 
      hAgo2-RISC activation. Consistently, genetic depletion of C3PO compromised RNA 
      silencing in mammalian cells. We determined the crystal structure of hC3PO, which 
      reveals an asymmetric octamer barrel consisting of six translin and two TRAX 
      subunits. This asymmetric assembly is critical for the function of C3PO as an 
      endonuclease that cleaves RNA at the interior surface. The current work supports 
      a Dicer-independent mechanism for human RISC activation, in which Ago2 directly 
      binds duplex siRNA and nicks the passenger strand, and then C3PO activates RISC 
      by degrading the Ago2-nicked passenger strand.
FAU - Ye, Xuecheng
AU  - Ye X
AD  - Department of Biochemistry, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Huang, Nian
AU  - Huang N
FAU - Liu, Ying
AU  - Liu Y
FAU - Paroo, Zain
AU  - Paroo Z
FAU - Huerta, Carlos
AU  - Huerta C
FAU - Li, Peng
AU  - Li P
FAU - Chen, She
AU  - Chen S
FAU - Liu, Qinghua
AU  - Liu Q
FAU - Zhang, Hong
AU  - Zhang H
LA  - eng
SI  - PDB/3PJA
SI  - PDB/3QB5
GR  - RC1 GM091286-01/GM/NIGMS NIH HHS/United States
GR  - RC1 GM091286-02/GM/NIGMS NIH HHS/United States
GR  - GM084010/GM/NIGMS NIH HHS/United States
GR  - R01 GM084010-03/GM/NIGMS NIH HHS/United States
GR  - R01 GM084010/GM/NIGMS NIH HHS/United States
GR  - GM091286/GM/NIGMS NIH HHS/United States
GR  - RC1 GM091286/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110508
PL  - United States
TA  - Nat Struct Mol Biol
JT  - Nature structural & molecular biology
JID - 101186374
RN  - 0 (AGO2 protein, human)
RN  - 0 (Argonaute Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (TSN protein, human)
RN  - 0 (TSNAX protein, human)
RN  - EC 3.1.- (Endoribonucleases)
RN  - EC 3.4.- (Carboxypeptidases)
RN  - EC 3.4.16.- (SCPEP1 protein, human)
SB  - IM
MH  - Argonaute Proteins
MH  - Carboxypeptidases/*biosynthesis
MH  - Crystallography, X-Ray
MH  - DNA-Binding Proteins/chemistry/*metabolism
MH  - Endoribonucleases/chemistry/*metabolism
MH  - Eukaryotic Initiation Factor-2/*metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Protein Binding
MH  - Protein Structure, Quaternary
MH  - RNA, Small Interfering/*metabolism
PMC - PMC3109212
MID - NIHMS271445
EDAT- 2011/05/10 06:00
MHDA- 2011/06/21 06:00
PMCR- 2011/12/01
CRDT- 2011/05/10 06:00
PHST- 2010/09/11 00:00 [received]
PHST- 2011/02/08 00:00 [accepted]
PHST- 2011/05/10 06:00 [entrez]
PHST- 2011/05/10 06:00 [pubmed]
PHST- 2011/06/21 06:00 [medline]
PHST- 2011/12/01 00:00 [pmc-release]
AID - nsmb.2032 [pii]
AID - 10.1038/nsmb.2032 [doi]
PST - ppublish
SO  - Nat Struct Mol Biol. 2011 Jun;18(6):650-7. doi: 10.1038/nsmb.2032. Epub 2011 May 
      8.