Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2

Brittany J. Lee; Ahmet E. Cansizoglu; Katherine E. Süel; Thomas H. Louis; Zichao Zhang; Yuh Min Chook

doi:10.1016/j.cell.2006.05.049

Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2

Brittany J. Lee, Ahmet E. Cansizoglu, Katherine E. Süel, Thomas H. Louis, Zichao Zhang, Yuh Min Chook

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

442 Scopus citations

Abstract

Karyopherinβ (Kapβ) proteins bind nuclear localization and export signals (NLSs and NESs) to mediate nucleocytoplasmic trafficking, a process regulated by Ran GTPase through its nucleotide cycle. Diversity and complexity of signals recognized by Kapβs have prevented prediction of new Kapβ substrates. The structure of Kapβ2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase. Further analyses reveal three rules for NLS recognition by Kapβ2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX_(2-5)PY consensus sequence. We demonstrate the predictive nature of these rules by identifying NLSs in seven previously known Kapβ2 substrates and uncovering 81 new candidate substrates, confirming five experimentally. These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone.

Original language	English (US)
Pages (from-to)	543-558
Number of pages	16
Journal	Cell
Volume	126
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2006.05.049
State	Published - Aug 4 2006

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2006.05.049

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@article{323a712d4a114c46b7b43dcb0bd432ef,

title = "Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2",

abstract = "Karyopherinβ (Kapβ) proteins bind nuclear localization and export signals (NLSs and NESs) to mediate nucleocytoplasmic trafficking, a process regulated by Ran GTPase through its nucleotide cycle. Diversity and complexity of signals recognized by Kapβs have prevented prediction of new Kapβ substrates. The structure of Kapβ2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase. Further analyses reveal three rules for NLS recognition by Kapβ2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence. We demonstrate the predictive nature of these rules by identifying NLSs in seven previously known Kapβ2 substrates and uncovering 81 new candidate substrates, confirming five experimentally. These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone.",

author = "Lee, {Brittany J.} and Cansizoglu, {Ahmet E.} and S{\"u}el, {Katherine E.} and Louis, {Thomas H.} and Zichao Zhang and Chook, {Yuh Min}",

note = "Funding Information: We thank UT Southwestern SBL for technical advice and assistance in data collection; C. Thomas for advice on ITC; D. Schmidt, H. Gu, and L. Motta-Mena for assistance in protein expression and purification; N. Grishin for help with bioinformatics; G. Blobel for support of the initial stage of this project; and Z. Otwinowski, M. Phillips, S. Sprang, K. Gardner, R. Ranganathan, and M. Rosen for discussion. The U. S. Department of Energy, Office of Science, and Office of Basic Energy Sciences, under Contract No W-31-109-ENG-38, supported use of the Advanced Photon Source. NIH-R01 GM069909, Welch Foundation Grant I-1532, and the UT Southwestern Endowed Scholars Program support this work. ",

year = "2006",

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doi = "10.1016/j.cell.2006.05.049",

language = "English (US)",

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T1 - Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2

AU - Lee, Brittany J.

AU - Cansizoglu, Ahmet E.

AU - Süel, Katherine E.

AU - Louis, Thomas H.

AU - Zhang, Zichao

AU - Chook, Yuh Min

N1 - Funding Information: We thank UT Southwestern SBL for technical advice and assistance in data collection; C. Thomas for advice on ITC; D. Schmidt, H. Gu, and L. Motta-Mena for assistance in protein expression and purification; N. Grishin for help with bioinformatics; G. Blobel for support of the initial stage of this project; and Z. Otwinowski, M. Phillips, S. Sprang, K. Gardner, R. Ranganathan, and M. Rosen for discussion. The U. S. Department of Energy, Office of Science, and Office of Basic Energy Sciences, under Contract No W-31-109-ENG-38, supported use of the Advanced Photon Source. NIH-R01 GM069909, Welch Foundation Grant I-1532, and the UT Southwestern Endowed Scholars Program support this work.

PY - 2006/8/4

Y1 - 2006/8/4

N2 - Karyopherinβ (Kapβ) proteins bind nuclear localization and export signals (NLSs and NESs) to mediate nucleocytoplasmic trafficking, a process regulated by Ran GTPase through its nucleotide cycle. Diversity and complexity of signals recognized by Kapβs have prevented prediction of new Kapβ substrates. The structure of Kapβ2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase. Further analyses reveal three rules for NLS recognition by Kapβ2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence. We demonstrate the predictive nature of these rules by identifying NLSs in seven previously known Kapβ2 substrates and uncovering 81 new candidate substrates, confirming five experimentally. These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone.

AB - Karyopherinβ (Kapβ) proteins bind nuclear localization and export signals (NLSs and NESs) to mediate nucleocytoplasmic trafficking, a process regulated by Ran GTPase through its nucleotide cycle. Diversity and complexity of signals recognized by Kapβs have prevented prediction of new Kapβ substrates. The structure of Kapβ2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase. Further analyses reveal three rules for NLS recognition by Kapβ2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence. We demonstrate the predictive nature of these rules by identifying NLSs in seven previously known Kapβ2 substrates and uncovering 81 new candidate substrates, confirming five experimentally. These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone.

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Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2

Abstract

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