Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

Giuseppe Nicastro; María Flor García-Mayoral; David Hollingworth; Geoff Kelly; Stephen R. Martin; Paola Briata; Roberto Gherzi; Andres Ramos

doi:10.1038/nsmb.2427

Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

Giuseppe Nicastro, María Flor García-Mayoral, David Hollingworth, Geoff Kelly, Stephen R. Martin, Paola Briata, Roberto Gherzi, Andres Ramos

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre-let-7 terminal loop and dominates the interaction. The structure of the KH3-RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.

Original language	English
Pages (from-to)	1282-1286
Number of pages	5
Journal	Nature Structural and Molecular Biology
Volume	19
Issue number	12
DOIs	https://doi.org/10.1038/nsmb.2427
State	Published - Dec 2012
Externally published	Yes

Access to Document

10.1038/nsmb.2427

Cite this

@article{338f6cb38eaa453e95a81f05d2a5a059,

title = "Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis",

abstract = "Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre-let-7 terminal loop and dominates the interaction. The structure of the KH3-RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.",

author = "Giuseppe Nicastro and Garc{\'i}a-Mayoral, {Mar{\'i}a Flor} and David Hollingworth and Geoff Kelly and Martin, {Stephen R.} and Paola Briata and Roberto Gherzi and Andres Ramos",

note = "Funding Information: All the NMR experiments were recorded at the Medical Research Council Biomedical NMR Centre at the Medical Research Council National Institute for Medical Research, and we thank T. Frenkiel and A. Oregioni for assistance. We thank S. Howell for mass spectrometry analysis of protein samples. The work of A.R. has been funded by the Medical Research Council (MRC) grant U117574558 and the Wellcome Trust Grant WT082088MA. The work of S.R.M. and G.K. has been funded by MRC grants U117570592 and U117533887, respectively. The work of P.B. and R.G. has been supported by grants from the Association for International Cancer Research (10-0527) and Associazione Italiana per la Ricerca sul Cancro (I.G. 10090). We thank B. Faust for help in the expression and purification of the KH3 K368R mutant.",

year = "2012",

month = dec,

doi = "10.1038/nsmb.2427",

language = "English",

volume = "19",

pages = "1282--1286",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "Nature Research",

number = "12",

}

TY - JOUR

T1 - Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

AU - Nicastro, Giuseppe

AU - García-Mayoral, María Flor

AU - Hollingworth, David

AU - Kelly, Geoff

AU - Martin, Stephen R.

AU - Briata, Paola

AU - Gherzi, Roberto

AU - Ramos, Andres

N1 - Funding Information: All the NMR experiments were recorded at the Medical Research Council Biomedical NMR Centre at the Medical Research Council National Institute for Medical Research, and we thank T. Frenkiel and A. Oregioni for assistance. We thank S. Howell for mass spectrometry analysis of protein samples. The work of A.R. has been funded by the Medical Research Council (MRC) grant U117574558 and the Wellcome Trust Grant WT082088MA. The work of S.R.M. and G.K. has been funded by MRC grants U117570592 and U117533887, respectively. The work of P.B. and R.G. has been supported by grants from the Association for International Cancer Research (10-0527) and Associazione Italiana per la Ricerca sul Cancro (I.G. 10090). We thank B. Faust for help in the expression and purification of the KH3 K368R mutant.

PY - 2012/12

Y1 - 2012/12

N2 - Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre-let-7 terminal loop and dominates the interaction. The structure of the KH3-RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.

AB - Let-7 is an important tumor-suppressive microRNA (miRNA) that acts as an on-off switch for cellular differentiation and regulates the expression of a set of human oncogenes. Binding of the human KSRP protein to let-7 miRNA precursors positively regulates their processing to mature let-7, thereby contributing to control of cell proliferation, apoptosis and differentiation. Here we analyze the molecular basis for KSRP-let-7 precursor selectivity and show how the third KH domain of the protein recognizes a G-rich sequence in the pre-let-7 terminal loop and dominates the interaction. The structure of the KH3-RNA complex explains the protein recognition of this noncanonical KH target sequence, and we demonstrate that the specificity of this binding is crucial for the functional interaction between the protein and the miRNA precursor.

UR - http://www.scopus.com/inward/record.url?scp=84870824218&partnerID=8YFLogxK

U2 - 10.1038/nsmb.2427

DO - 10.1038/nsmb.2427

M3 - Article

C2 - 23142982

AN - SCOPUS:84870824218

SN - 1545-9993

VL - 19

SP - 1282

EP - 1286

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 12

ER -

Noncanonical G recognition mediates KSRP regulation of let-7 biogenesis

Abstract

Access to Document

Fingerprint

Cite this