LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA

Isabel Cruz-Gallardo; Luigi Martino; Geoff Kelly; R Andrew Atkinson; Roberta Trotta; Stefano De Tito; Pierre Coleman; Zainab Ahdash; Yifei Gu; Tam T T Bui; Maria R Conte

doi:10.1093/nar/gkz144

LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA

Isabel Cruz-Gallardo, Luigi Martino, Geoff Kelly, R Andrew Atkinson, Roberta Trotta, Stefano De Tito, Pierre Coleman, Zainab Ahdash, Yifei Gu, Tam T T Bui, Maria R Conte

Francis Crick Institute

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27 Citations (Scopus)

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Abstract

LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A-oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein-protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.

Original language	English
Pages (from-to)	4272–4291
Number of pages	20
Journal	Nucleic Acids Research
Volume	47
Issue number	8
Early online date	1 Mar 2019
DOIs	https://doi.org/10.1093/nar/gkz144
Publication status	Published - 7 May 2019

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10.1093/nar/gkz144Licence: CC BY

LARP4A recognizes polyA RNA_CRUZ-GALLARDO_Accepted19Feb2019_GOLD VoRFinal published version, 5.72 MBLicence: CC BY

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Cruz-Gallardo, I., Martino, L., Kelly, G., Atkinson, R. A., Trotta, R., De Tito, S., Coleman, P., Ahdash, Z., Gu, Y., Bui, T. T. T., & Conte, M. R. (2019). LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA. Nucleic Acids Research, 47(8), 4272–4291. https://doi.org/10.1093/nar/gkz144

@article{a3b0f11132d84cdea39335c5c144c8a9,

title = "LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA",

abstract = "LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A-oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein-protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.",

author = "Isabel Cruz-Gallardo and Luigi Martino and Geoff Kelly and Atkinson, {R Andrew} and Roberta Trotta and {De Tito}, Stefano and Pierre Coleman and Zainab Ahdash and Yifei Gu and Bui, {Tam T T} and Conte, {Maria R}",

note = "{\textcopyright} The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.",

year = "2019",

month = may,

day = "7",

doi = "10.1093/nar/gkz144",

language = "English",

volume = "47",

pages = "4272–4291",

journal = "Nucleic Acids Research",

issn = "0305-1048",

publisher = "Oxford Univerity Press; Oxford",

number = "8",

}

Cruz-Gallardo, I , Martino, L, Kelly, G, Atkinson, RA, Trotta, R, De Tito, S, Coleman, P , Ahdash, Z , Gu, Y , Bui, TTT & Conte, MR 2019, 'LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA', Nucleic Acids Research, vol. 47, no. 8, pp. 4272–4291. https://doi.org/10.1093/nar/gkz144

LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA. / Cruz-Gallardo, Isabel ; Martino, Luigi; Kelly, Geoff et al.
In: Nucleic Acids Research, Vol. 47, No. 8, 07.05.2019, p. 4272–4291.

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

TY - JOUR

T1 - LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA

AU - Cruz-Gallardo, Isabel

AU - Martino, Luigi

AU - Kelly, Geoff

AU - Atkinson, R Andrew

AU - Trotta, Roberta

AU - De Tito, Stefano

AU - Coleman, Pierre

AU - Ahdash, Zainab

AU - Gu, Yifei

AU - Bui, Tam T T

AU - Conte, Maria R

PY - 2019/5/7

Y1 - 2019/5/7

N2 - LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A-oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein-protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.

AB - LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A-oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein-protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.

UR - http://www.scopus.com/inward/record.url?scp=85068537735&partnerID=8YFLogxK

U2 - 10.1093/nar/gkz144

DO - 10.1093/nar/gkz144

M3 - Article

C2 - 30820564

SN - 0305-1048

VL - 47

SP - 4272

EP - 4291

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 8

ER -

LARP4A recognizes polyA RNA via a novel binding mechanism mediated by disordered regions and involving the PAM2w motif, revealing interplay between PABP, LARP4A and mRNA

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