Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Kuntal Pal; Abhishek Bandyopadhyay; X. Edward Zhou; Qingping Xu; David P. Marciano; Joseph S. Brunzelle; Smitha Yerrum; Patrick R. Griffin; George Vande Woude; Karsten Melcher; H. Eric Xu

doi:10.1016/j.str.2017.04.015

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Kuntal Pal, Abhishek Bandyopadhyay, X. Edward Zhou, Qingping Xu, David P. Marciano, Joseph S. Brunzelle, Smitha Yerrum, Patrick R. Griffin, George Vande Woude, Karsten Melcher^*, H. Eric Xu

^*Corresponding author for this work

Pharmacology

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

16 Scopus citations

Abstract

The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2–142), the MET fusion partner of oncogenic TPR-MET. TPR(2–142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2–142) to the MET intracellular domain strongly and selectively stabilizes the αG helix of the MET kinase domain, and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.

Original language	English (US)
Pages (from-to)	867-877.e3
Journal	Structure
Volume	25
Issue number	6
DOIs	https://doi.org/10.1016/j.str.2017.04.015
State	Published - Jun 6 2017

Funding

This research was supported by the Van Andel Research Institute (H.E.X. and K.M.), the NIH (R01 GM102545 and GM104212 to K.M. and DK071662 to H.E.X.), the National Natural Science Foundation of China (31300245 to H.E.X.), Ministry of Science and Technology (China) grants 2012ZX09301001, 2012CB910403, 2013CB910600, XDB08020303, and 2013ZX09507001 (H.E.X), and Amway (China) (H.E.X.). We thank Michelle Martin for administrative support and staff members of the Life Science Collaborative Access Team of the Advanced Photon Source (APS) for assistance in data collection at the beamlines of sector 21, which is in part funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Use of APS was supported by the Office of Science of the US Department of Energy, under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Keywords

MET
oncogenic fusion kinase
receptor dimerization
receptor tyrosine kinase

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/j.str.2017.04.015

Cite this

@article{5ecd1fafe0c745109a6f58abd50bd04c,

title = "Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases",

abstract = "The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2–142), the MET fusion partner of oncogenic TPR-MET. TPR(2–142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2–142) to the MET intracellular domain strongly and selectively stabilizes the αG helix of the MET kinase domain, and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.",

keywords = "MET, oncogenic fusion kinase, receptor dimerization, receptor tyrosine kinase",

author = "Kuntal Pal and Abhishek Bandyopadhyay and Zhou, {X. Edward} and Qingping Xu and Marciano, {David P.} and Brunzelle, {Joseph S.} and Smitha Yerrum and Griffin, {Patrick R.} and {Vande Woude}, George and Karsten Melcher and Xu, {H. Eric}",

note = "Funding Information: This research was supported by the Van Andel Research Institute (H.E.X. and K.M.), the NIH (R01 GM102545 and GM104212 to K.M. and DK071662 to H.E.X.), the National Natural Science Foundation of China (31300245 to H.E.X.), Ministry of Science and Technology (China) grants 2012ZX09301001, 2012CB910403, 2013CB910600, XDB08020303, and 2013ZX09507001 (H.E.X), and Amway (China) (H.E.X.). We thank Michelle Martin for administrative support and staff members of the Life Science Collaborative Access Team of the Advanced Photon Source (APS) for assistance in data collection at the beamlines of sector 21, which is in part funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Use of APS was supported by the Office of Science of the US Department of Energy, under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = jun,

day = "6",

doi = "10.1016/j.str.2017.04.015",

language = "English (US)",

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T1 - Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

AU - Pal, Kuntal

AU - Bandyopadhyay, Abhishek

AU - Zhou, X. Edward

AU - Xu, Qingping

AU - Marciano, David P.

AU - Brunzelle, Joseph S.

AU - Yerrum, Smitha

AU - Griffin, Patrick R.

AU - Vande Woude, George

AU - Melcher, Karsten

AU - Xu, H. Eric

N1 - Funding Information: This research was supported by the Van Andel Research Institute (H.E.X. and K.M.), the NIH (R01 GM102545 and GM104212 to K.M. and DK071662 to H.E.X.), the National Natural Science Foundation of China (31300245 to H.E.X.), Ministry of Science and Technology (China) grants 2012ZX09301001, 2012CB910403, 2013CB910600, XDB08020303, and 2013ZX09507001 (H.E.X), and Amway (China) (H.E.X.). We thank Michelle Martin for administrative support and staff members of the Life Science Collaborative Access Team of the Advanced Photon Source (APS) for assistance in data collection at the beamlines of sector 21, which is in part funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Use of APS was supported by the Office of Science of the US Department of Energy, under Contract No. DE-AC02-06CH11357. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017/6/6

Y1 - 2017/6/6

N2 - The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2–142), the MET fusion partner of oncogenic TPR-MET. TPR(2–142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2–142) to the MET intracellular domain strongly and selectively stabilizes the αG helix of the MET kinase domain, and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.

AB - The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2–142), the MET fusion partner of oncogenic TPR-MET. TPR(2–142) contains a continuous 124-residue α helix that forms an antiparallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2–142) to the MET intracellular domain strongly and selectively stabilizes the αG helix of the MET kinase domain, and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.

KW - MET

KW - oncogenic fusion kinase

KW - receptor dimerization

KW - receptor tyrosine kinase

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DO - 10.1016/j.str.2017.04.015

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AN - SCOPUS:85019386802

SN - 0969-2126

VL - 25

SP - 867-877.e3

JO - Structure

JF - Structure

IS - 6

ER -

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Abstract

Funding

Keywords

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Structure of the TPR oligomerization domain

Structure of the TPR oligomerization domain

Structure of the TPR oligomerization domain

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Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

Structure of the TPR oligomerization domain

Structure of the TPR oligomerization domain

Structure of the TPR oligomerization domain

Cite this