Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase

Abstract

Choline kinase alpha is a 457-residue protein that catalyzes the reaction between ATP and choline to yield ADP and phosphocholine. This metabolic action has been well studied because of choline kinase’s link to cancer malignancy and poor patient prognosis. As the myriad of x-ray crystal structures available for this enzyme show, chemotherapeutic drug design has centered on stopping the catalytic activity of choline kinase and reducing the downstream metabolites it produces. Furthermore, these crystal structures only reveal the catalytic domain of the protein, residues 80–457. However, recent studies provide evidence for a non-catalytic protein-binding role for choline kinase alpha. Here, we show that choline kinase alpha interacts with the SH3 domain of c-Src. Co-precipitation assays, surface plasmon resonance, and crystallographic analysis of a 1.5 Å structure demonstrate that this interaction is specific and is mediated by the poly-proline region found N-terminal to the catalytic domain of choline kinase. Taken together, these data offer strong evidence that choline kinase alpha has a heretofore underappreciated role in protein-protein interactions, which offers an exciting new way to approach drug development against this cancer-enhancing protein.

Authors:
 [1];  [2];  [2];  [3]
+ Show Author Affiliations
  1. Univ. of Illinois, Chicago, IL (United States)
  2. University of Pittsburgh School of Medicine, PA (United States)
  3. Univ. of Illinois, Chicago, IL (United States); Jesse Brown VA Medical Center, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); US Department of Veteran Affairs; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of General Medical Sciences (NIGMS); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
OSTI Identifier:
1578228
Grant/Contract Number:  
AC02-06CH11357; R01EB013685; I01BX001919; DE018381; GM088119; 085P1000817
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; proteins; structural biology

Citation Formats

Kall, Stefanie L., Whitlatch, Kindra, Smithgall, Thomas E., and Lavie, Arnon. Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase. United States: N. p., 2019. Web. doi:10.1038/s41598-019-53447-0.
Copy to clipboard
Kall, Stefanie L., Whitlatch, Kindra, Smithgall, Thomas E., & Lavie, Arnon. Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase. United States. https://doi.org/10.1038/s41598-019-53447-0
Copy to clipboard
Kall, Stefanie L., Whitlatch, Kindra, Smithgall, Thomas E., and Lavie, Arnon. Tue . "Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase". United States. https://doi.org/10.1038/s41598-019-53447-0. https://www.osti.gov/servlets/purl/1578228.
Copy to clipboard
@article{osti_1578228,
title = {Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase},
author = {Kall, Stefanie L. and Whitlatch, Kindra and Smithgall, Thomas E. and Lavie, Arnon},
abstractNote = {Choline kinase alpha is a 457-residue protein that catalyzes the reaction between ATP and choline to yield ADP and phosphocholine. This metabolic action has been well studied because of choline kinase’s link to cancer malignancy and poor patient prognosis. As the myriad of x-ray crystal structures available for this enzyme show, chemotherapeutic drug design has centered on stopping the catalytic activity of choline kinase and reducing the downstream metabolites it produces. Furthermore, these crystal structures only reveal the catalytic domain of the protein, residues 80–457. However, recent studies provide evidence for a non-catalytic protein-binding role for choline kinase alpha. Here, we show that choline kinase alpha interacts with the SH3 domain of c-Src. Co-precipitation assays, surface plasmon resonance, and crystallographic analysis of a 1.5 Å structure demonstrate that this interaction is specific and is mediated by the poly-proline region found N-terminal to the catalytic domain of choline kinase. Taken together, these data offer strong evidence that choline kinase alpha has a heretofore underappreciated role in protein-protein interactions, which offers an exciting new way to approach drug development against this cancer-enhancing protein.},
doi = {10.1038/s41598-019-53447-0},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United States},
year = {Tue Nov 19 00:00:00 EST 2019},
month = {Tue Nov 19 00:00:00 EST 2019}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1038/s41598-019-53447-0
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 5 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling
journal, October 2009

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism
journal, July 2016

Identification of a Unique Inhibitor-Binding Site on Choline Kinase α
journal, February 2018

Choline kinase inhibitors as a novel approach for antiproliferative drug design
journal, November 1997

  • Hernández-Alcoceba, Rubén; Saniger, Luisa; Campos, Joaquín
  • Oncogene, Vol. 15, Issue 19
  • DOI: 10.1038/sj.onc.1201414

The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases
journal, April 2017

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3: SINGLE AMINO ACID NEAR THE ACTIVE SITE INFLUENCES INHIBITOR SENSITIVITY
journal, March 2010

  • Hong, Bum Soo; Allali-Hassani, Abdellah; Tempel, Wolfram
  • Journal of Biological Chemistry, Vol. 285, Issue 21
  • DOI: 10.1074/jbc.M109.039024

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis
journal, December 2005

  • Sher, Roger B.; Aoyama, Chieko; Huebsch, Kimberly A.
  • Journal of Biological Chemistry, Vol. 281, Issue 8
  • DOI: 10.1074/jbc.M512578200

Elucidation of Human Choline Kinase Crystal Structures in Complex with the Products ADP or Phosphocholine
journal, November 2006

  • Malito, Enrico; Sekulic, Nikolina; Too, Wei Cun See
  • Journal of Molecular Biology, Vol. 364, Issue 2
  • DOI: 10.1016/j.jmb.2006.08.084

The growth and characterization of membrane protein crystals
journal, August 1986

  • Garavito, R. Michael; Markovic-Housley, Zora; Jenkins, John A.
  • Journal of Crystal Growth, Vol. 76, Issue 3
  • DOI: 10.1016/0022-0248(86)90187-9

The src protein contains multiple domains for specific attachment to membranes.
journal, March 1990

  • Kaplan, J. M.; Varmus, H. E.; Bishop, J. M.
  • Molecular and Cellular Biology, Vol. 10, Issue 3
  • DOI: 10.1128/MCB.10.3.1000

Src Kinases Mediate STAT Growth Pathways in Squamous Cell Carcinoma of the Head and Neck
journal, May 2003

  • Xi, Sichuan; Zhang, Qing; Dyer, Kevin F.
  • Journal of Biological Chemistry, Vol. 278, Issue 34
  • DOI: 10.1074/jbc.M303499200

Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice
journal, May 2009

  • Wu, Gengshu; Sher, Roger B.; Cox, Gregory A.
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1791, Issue 5
  • DOI: 10.1016/j.bbalip.2009.02.006

The SH3 domain- a family of versatile peptide- and protein-recognition module
journal, January 2008

  • Kaneko, Tomonori
  • Frontiers in Bioscience, Vol. Volume, Issue 13
  • DOI: 10.2741/3053

Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy
journal, June 2002

  • Ramírez de Molina, Ana; Gutiérrez, Ruth; Ramos, Maria Angeles
  • Oncogene, Vol. 21, Issue 27
  • DOI: 10.1038/sj.onc.1205556

XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

A ligase-mediated gene detection technique
journal, August 1988

NIH Image to ImageJ: 25 years of image analysis
journal, June 2012

  • Schneider, Caroline A.; Rasband, Wayne S.; Eliceiri, Kevin W.
  • Nature Methods, Vol. 9, Issue 7
  • DOI: 10.1038/nmeth.2089

Polyproline-II Helix in Proteins: Structure and Function
journal, June 2013

  • Adzhubei, Alexei A.; Sternberg, Michael J. E.; Makarov, Alexander A.
  • Journal of Molecular Biology, Vol. 425, Issue 12
  • DOI: 10.1016/j.jmb.2013.03.018

Let's get specific: the relationship between specificity and affinity
journal, October 1995

Signaling by the Germinal Center Kinase Family of Protein Kinases
journal, February 1999

SDS-PAGE of Proteins
journal, June 2006

Structure and function of choline kinase isoforms in mammalian cells
journal, May 2004

Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1
journal, June 2015

  • Serrán-Aguilera, Lucía; Nuti, Roberto; López-Cara, Luisa C.
  • Molecular Informatics, Vol. 34, Issue 6-7
  • DOI: 10.1002/minf.201400140

Biochemical characterization of the initial steps of the Kennedy pathway in Trypanosoma brucei: the ethanolamine and choline kinases
journal, September 2008

  • Gibellini, Federica; Hunter, William N.; Smith, Terry K.
  • Biochemical Journal, Vol. 415, Issue 1
  • DOI: 10.1042/BJ20080435

Identification and characterization of Src SH3 ligands from phage-displayed random peptide libraries.
journal, September 1994

Choline kinase inhibition in rheumatoid arthritis
journal, October 2014

Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells
journal, December 2008

  • Banez-Coronel, Monica; de Molina, Ana; Rodriguez-Gonzalez, Agustin
  • Current Cancer Drug Targets, Vol. 8, Issue 8
  • DOI: 10.2174/156800908786733432

Cellular Functions Regulated by src Family Kinases
journal, November 1997

Computational Analysis and Prediction of the Binding Motif and Protein Interacting Partners of the Abl SH3 Domain
journal, January 2006

Protein production by auto-induction in high-density shaking cultures
journal, May 2005

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement
journal, August 2014

Striving for purity: advances in protein purification
journal, January 2005

Structure of the c-Src-SH3 domain in complex with a proline-rich motif of NS5A protein from the hepatitis C virus
journal, January 2015

  • Bacarizo, Julio; Martínez-Rodríguez, Sergio; Cámara-Artigas, Ana
  • Journal of Structural Biology, Vol. 189, Issue 1
  • DOI: 10.1016/j.jsb.2014.11.004

Choline metabolism in malignant transformation
journal, November 2011

  • Glunde, Kristine; Bhujwalla, Zaver M.; Ronen, Sabrina M.
  • Nature Reviews Cancer, Vol. 11, Issue 12
  • DOI: 10.1038/nrc3162

Distinct ligand preferences of Src homology 3 domains from Src, Yes, Abl, Cortactin, p53bp2, PLCgamma, Crk, and Grb2.
journal, February 1996

  • Sparks, A. B.; Rider, J. E.; Hoffman, N. G.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 4
  • DOI: 10.1073/pnas.93.4.1540

Structure-activity aspects of hemicholinium-3 (HC-3) and its analogs and congeners
journal, September 1994

A non-catalytic role of choline kinase alpha is important in promoting cancer cell survival
journal, March 2013

Three-dimensional structure of the tyrosine kinase c-Src
journal, February 1997

  • Xu, Wenqing; Harrison, Stephen C.; Eck, Michael J.
  • Nature, Vol. 385, Issue 6617
  • DOI: 10.1038/385595a0

Kinetic and mechanistic characterisation of Choline Kinase-α
journal, June 2013

  • Hudson, Catherine S.; Knegtel, Ronald M.; Brown, Kieron
  • Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 6
  • DOI: 10.1016/j.bbapap.2013.02.008

Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production
journal, June 2019

Structure-activity aspects of hemicholinium-3 (HC-3) and its analogs and congeners
journal, September 1994

Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase α1
journal, June 2015

  • Serrán-Aguilera, Lucía; Nuti, Roberto; López-Cara, Luisa C.
  • Molecular Informatics, Vol. 34, Issue 6-7
  • DOI: 10.1002/minf.201400140

Drilling accurate nanopores for biosensors by energetic multi-wall carbon nanotubes: a molecular dynamics investigation
journal, September 2022

The growth and characterization of membrane protein crystals
journal, August 1986

  • Garavito, R. Michael; Markovic-Housley, Zora; Jenkins, John A.
  • Journal of Crystal Growth, Vol. 76, Issue 3
  • DOI: 10.1016/0022-0248(86)90187-9

Let's get specific: the relationship between specificity and affinity
journal, October 1995

Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice
journal, May 2009

  • Wu, Gengshu; Sher, Roger B.; Cox, Gregory A.
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1791, Issue 5
  • DOI: 10.1016/j.bbalip.2009.02.006

Kinetic and mechanistic characterisation of Choline Kinase-α
journal, June 2013

  • Hudson, Catherine S.; Knegtel, Ronald M.; Brown, Kieron
  • Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Vol. 1834, Issue 6
  • DOI: 10.1016/j.bbapap.2013.02.008

Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production
journal, June 2019

Elucidation of Human Choline Kinase Crystal Structures in Complex with the Products ADP or Phosphocholine
journal, November 2006

  • Malito, Enrico; Sekulic, Nikolina; Too, Wei Cun See
  • Journal of Molecular Biology, Vol. 364, Issue 2
  • DOI: 10.1016/j.jmb.2006.08.084

Polyproline-II Helix in Proteins: Structure and Function
journal, June 2013

  • Adzhubei, Alexei A.; Sternberg, Michael J. E.; Makarov, Alexander A.
  • Journal of Molecular Biology, Vol. 425, Issue 12
  • DOI: 10.1016/j.jmb.2013.03.018

Structure of the c-Src-SH3 domain in complex with a proline-rich motif of NS5A protein from the hepatitis C virus
journal, January 2015

  • Bacarizo, Julio; Martínez-Rodríguez, Sergio; Cámara-Artigas, Ana
  • Journal of Structural Biology, Vol. 189, Issue 1
  • DOI: 10.1016/j.jsb.2014.11.004

Structure and function of choline kinase isoforms in mammalian cells
journal, May 2004

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism
journal, July 2016

The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases
journal, April 2017

Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers
journal, August 2002

  • Ramı́rez de Molina, Ana; Rodrı́guez-González, Agustı́n; Gutiérrez, Ruth
  • Biochemical and Biophysical Research Communications, Vol. 296, Issue 3
  • DOI: 10.1016/s0006-291x(02)00920-8

Monosialyl-Gb5 organized with cSrc and FAK in GEM of human breast carcinoma MCF-7 cells defines their invasive properties
journal, October 2002

Choline Phosphokinase
journal, May 1953

Identification of a Unique Inhibitor-Binding Site on Choline Kinase α
journal, February 2018

Three-dimensional structure of the tyrosine kinase c-Src
journal, February 1997

  • Xu, Wenqing; Harrison, Stephen C.; Eck, Michael J.
  • Nature, Vol. 385, Issue 6617
  • DOI: 10.1038/385595a0

Choline metabolism in malignant transformation
journal, November 2011

  • Glunde, Kristine; Bhujwalla, Zaver M.; Ronen, Sabrina M.
  • Nature Reviews Cancer, Vol. 11, Issue 12
  • DOI: 10.1038/nrc3162

Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling
journal, October 2009

A non-catalytic role of choline kinase alpha is important in promoting cancer cell survival
journal, March 2013

Choline kinase inhibitors as a novel approach for antiproliferative drug design
journal, November 1997

  • Hernández-Alcoceba, Rubén; Saniger, Luisa; Campos, Joaquín
  • Oncogene, Vol. 15, Issue 19
  • DOI: 10.1038/sj.onc.1201414

Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy
journal, June 2002

  • Ramírez de Molina, Ana; Gutiérrez, Ruth; Ramos, Maria Angeles
  • Oncogene, Vol. 21, Issue 27
  • DOI: 10.1038/sj.onc.1205556

Distinct ligand preferences of Src homology 3 domains from Src, Yes, Abl, Cortactin, p53bp2, PLCgamma, Crk, and Grb2.
journal, February 1996

  • Sparks, A. B.; Rider, J. E.; Hoffman, N. G.
  • Proceedings of the National Academy of Sciences, Vol. 93, Issue 4
  • DOI: 10.1073/pnas.93.4.1540

Signaling by the Germinal Center Kinase Family of Protein Kinases
journal, February 1999

Choline Kinase β Mutant Mice Exhibit Reduced Phosphocholine, Elevated Osteoclast Activity, and Low Bone Mass
journal, December 2014

  • Kular, Jasreen; Tickner, Jennifer C.; Pavlos, Nathan J.
  • Journal of Biological Chemistry, Vol. 290, Issue 3
  • DOI: 10.1074/jbc.m114.567966

c-Src Regulation of Fibroblast Growth Factor-induced Proliferation in Murine Embryonic Fibroblasts
journal, March 2003

  • Kilkenny, Dawn M.; Rocheleau, Jonathan V.; Price, James
  • Journal of Biological Chemistry, Vol. 278, Issue 19
  • DOI: 10.1074/jbc.m209698200

SDS-PAGE of Proteins
journal, June 2006

MOLREP an Automated Program for Molecular Replacement
journal, December 1997

Antiplasmodial Activity and Mechanism of Action of RSM-932A, a Promising Synergistic Inhibitor of Plasmodium falciparum Choline Kinase
journal, September 2013

  • Zimmerman, Tahl; Moneriz, Carlos; Diez, Amalia
  • Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 12
  • DOI: 10.1128/aac.00920-13

The src Protein Contains Multiple Domains for Specific Attachment to Membranes
journal, March 1990

Choline kinase inhibition in rheumatoid arthritis
journal, October 2014

Cellular Functions Regulated by src Family Kinases
journal, November 1997

Choline Kinase Is a Novel Oncogene that Potentiates RhoA-Induced Carcinogenesis
journal, July 2005

RNA Interference–Mediated Choline Kinase Suppression in Breast Cancer Cells Induces Differentiation and Reduces Proliferation
journal, December 2005

Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer Cells
journal, February 2010

Computational Analysis and Prediction of the Binding Motif and Protein Interacting Partners of the Abl SH3 Domain
journal, January 2006

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement
journal, August 2014

Choline Kinase Alpha Depletion Selectively Kills Tumoral Cells
journal, December 2008

  • Banez-Coronel, Monica; de Molina, Ana; Rodriguez-Gonzalez, Agustin
  • Current Cancer Drug Targets, Vol. 8, Issue 8
  • DOI: 10.2174/156800908786733432

The SH3 domain- a family of versatile peptide- and protein-recognition module
journal, January 2008

  • Kaneko, Tomonori
  • Frontiers in Bioscience, Vol. Volume, Issue 13
  • DOI: 10.2741/3053
    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology
    journal, February 2022

      Sort by:
      [ × clear filter / sort ]

      Similar Records in DOE PAGES and OSTI.GOV collections: