Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome

Hal A. Lewis; Kiran Musunuru; Kirk B. Jensen; Carme Edo; Hua Chen; Robert B. Darnell; Stephen K. Burley

doi:10.1016/S0092-8674(00)80668-6

Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome

Hal A. Lewis, Kiran Musunuru, Kirk B. Jensen, Carme Edo, Hua Chen, Robert B. Darnell, Stephen K. Burley

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

282 Citations (Scopus)

Abstract

The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 Å resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic α helix/β sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.

Original language	English
Pages (from-to)	323-332
Number of pages	10
Journal	Cell
Volume	100
Issue number	3
DOIs	https://doi.org/10.1016/S0092-8674(00)80668-6
Publication status	Published or Issued - 4 Feb 2000
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1016/S0092-8674(00)80668-6

Cite this

@article{41341871ed364777a8df9e660d1e4e2f,

title = "Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome",

abstract = "The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 {\AA} resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic α helix/β sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.",

author = "Lewis, {Hal A.} and Kiran Musunuru and Jensen, {Kirk B.} and Carme Edo and Hua Chen and Darnell, {Robert B.} and Burley, {Stephen K.}",

note = "Funding Information: At the NSLS, we thank Dr. Lonny Berman for help using Beamline X25. At CHESS, we thank Dr. Dan Thiel and the MacCHESS staff for help using Beamline A1. We thank Drs. A. R. Ferr{\'e}-D'Amar{\'e}, J. B. Bonanno, R. J. Buckanovich, R. C. Deo, K. S. Gajiwala, D. Jeruzalmi, J. Kuriyan, J. Marcotrigiano, S. K. Nair, G. A. Petsko, S. Scaringe, N. Sonenberg, and Y. Y. L. Yang for many useful discussions. S. K. B. is an Investigator in the Howard Hughes Medical Institute. This work was supported in part by the Rockefeller University (S. K. B.) and the NIH (R. B. D.). K. M. was supported by the Cornell/Rockefeller/Sloan-Kettering Tri-Institutional M.D.–Ph.D. Program and NIH MSTP Grant GM07739. K. B. J. was supported by the Breast Cancer Research Program DAMD17-97-1-7097.",

year = "2000",

month = feb,

day = "4",

doi = "10.1016/S0092-8674(00)80668-6",

language = "English",

volume = "100",

pages = "323--332",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Sequence-specific RNA binding by a Nova KH domain

T2 - Implications for paraneoplastic disease and the fragile X syndrome

AU - Lewis, Hal A.

AU - Musunuru, Kiran

AU - Jensen, Kirk B.

AU - Edo, Carme

AU - Chen, Hua

AU - Darnell, Robert B.

AU - Burley, Stephen K.

N1 - Funding Information: At the NSLS, we thank Dr. Lonny Berman for help using Beamline X25. At CHESS, we thank Dr. Dan Thiel and the MacCHESS staff for help using Beamline A1. We thank Drs. A. R. Ferré-D'Amaré, J. B. Bonanno, R. J. Buckanovich, R. C. Deo, K. S. Gajiwala, D. Jeruzalmi, J. Kuriyan, J. Marcotrigiano, S. K. Nair, G. A. Petsko, S. Scaringe, N. Sonenberg, and Y. Y. L. Yang for many useful discussions. S. K. B. is an Investigator in the Howard Hughes Medical Institute. This work was supported in part by the Rockefeller University (S. K. B.) and the NIH (R. B. D.). K. M. was supported by the Cornell/Rockefeller/Sloan-Kettering Tri-Institutional M.D.–Ph.D. Program and NIH MSTP Grant GM07739. K. B. J. was supported by the Breast Cancer Research Program DAMD17-97-1-7097.

PY - 2000/2/4

Y1 - 2000/2/4

N2 - The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 Å resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic α helix/β sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.

AB - The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 Å resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic α helix/β sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.

UR - http://www.scopus.com/inward/record.url?scp=0034603208&partnerID=8YFLogxK

U2 - 10.1016/S0092-8674(00)80668-6

DO - 10.1016/S0092-8674(00)80668-6

M3 - Article

C2 - 10676814

AN - SCOPUS:0034603208

SN - 0092-8674

VL - 100

SP - 323

EP - 332

JO - Cell

JF - Cell

IS - 3

ER -

Sequence-specific RNA binding by a Nova KH domain: Implications for paraneoplastic disease and the fragile X syndrome

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this