Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ
Abstract
Signaling molecule phosphatidylinositol 4,5-bisphosphate is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3, caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Kγ. So far, the exact role of this aspartate residue has yet to be elucidated. As such, we conducted structural, functional and computational studies on a zebrafish PIP5Kα variant with a mutation at the same site. Compared with the structure of the wild-type (WT) protein in the ATP-bound state, the ATP-associating glycine-rich loop of the mutant protein was severely disordered and the temperature factor of ATP was significantly higher. Both observations suggest a greater degree of disorder of the bound ATP, whereas neither the structure of the catalytic site nor the Km toward ATP was substantially affected by the mutation. Microsecond molecular dynamics simulation revealed that negative charge elimination caused by the mutation destabilized the involved hydrogen bonds and affected key electrostatic interactions in the close proximity of ATP. Taken together, our data indicated that the disease-related aspartate residue is a key node in the interaction network crucial for effective ATPmore »
- Authors:
-
[1]
- Michigan State Univ., East Lansing, MI (United States)
- Yale School of Medicine, New Haven, CT (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1544882
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Biochemical Journal
- Additional Journal Information:
- Journal Volume: 475; Journal Issue: 14; Journal ID: ISSN 0264-6021
- Publisher:
- Biochemical Society
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; LCCS3; molecular dynamics simulation; phosphatidylinositol 4, 5-bisphosphate; phosphatidylinositol 4-phosphate 5-kinase; X-ray crystallography
Citation Formats
Zeng, Xuankun, Uyar, Arzu, Sui, Dexin, Donyapour, Nazanin, Wu, Dianqing, Dickson, Alex, and Hu, Jian. Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ. United States: N. p., 2018.
Web. doi:10.1042/bcj20180326.
Zeng, Xuankun, Uyar, Arzu, Sui, Dexin, Donyapour, Nazanin, Wu, Dianqing, Dickson, Alex, & Hu, Jian. Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ. United States. https://doi.org/10.1042/bcj20180326
Zeng, Xuankun, Uyar, Arzu, Sui, Dexin, Donyapour, Nazanin, Wu, Dianqing, Dickson, Alex, and Hu, Jian. Fri .
"Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ". United States. https://doi.org/10.1042/bcj20180326. https://www.osti.gov/servlets/purl/1544882.
@article{osti_1544882,
title = {Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ},
author = {Zeng, Xuankun and Uyar, Arzu and Sui, Dexin and Donyapour, Nazanin and Wu, Dianqing and Dickson, Alex and Hu, Jian},
abstractNote = {Signaling molecule phosphatidylinositol 4,5-bisphosphate is produced primarily by phosphatidylinositol 4-phosphate 5-kinase (PIP5K). PIP5K is essential for the development of the human neuronal system, which has been exemplified by a recessive genetic disorder, lethal congenital contractural syndrome type 3, caused by a single aspartate-to-asparagine mutation in the kinase domain of PIP5Kγ. So far, the exact role of this aspartate residue has yet to be elucidated. As such, we conducted structural, functional and computational studies on a zebrafish PIP5Kα variant with a mutation at the same site. Compared with the structure of the wild-type (WT) protein in the ATP-bound state, the ATP-associating glycine-rich loop of the mutant protein was severely disordered and the temperature factor of ATP was significantly higher. Both observations suggest a greater degree of disorder of the bound ATP, whereas neither the structure of the catalytic site nor the Km toward ATP was substantially affected by the mutation. Microsecond molecular dynamics simulation revealed that negative charge elimination caused by the mutation destabilized the involved hydrogen bonds and affected key electrostatic interactions in the close proximity of ATP. Taken together, our data indicated that the disease-related aspartate residue is a key node in the interaction network crucial for effective ATP binding. This work provides a paradigm of how a subtle but critical structural perturbation caused by a single mutation at the ATP-binding site abolishes the kinase activity, emphasizing that stabilizing substrate in a productive conformational state is crucial for catalysis.},
doi = {10.1042/bcj20180326},
journal = {Biochemical Journal},
number = 14,
volume = 475,
place = {United States},
year = {Fri Jun 29 00:00:00 EDT 2018},
month = {Fri Jun 29 00:00:00 EDT 2018}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 4 works
Citation information provided by
Web of Science
Web of Science
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:
Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking
journal, September 2004
- Paolo, Gilbert Di; Moskowitz, Howard S.; Gipson, Keith
- Nature, Vol. 431, Issue 7007
PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions
journal, November 2009
- van den Bout, I.; Divecha, N.
- Journal of Cell Science, Vol. 122, Issue 21
Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled
journal, September 2015
- Hu, Jian; Yuan, Qianying; Kang, Xue
- Nature Communications, Vol. 6, Issue 1
Loss of PIP5KIγ, unlike other PIP5KI isoforms, impairs the integrity of the membrane cytoskeleton in murine megakaryocytes
journal, January 2008
- Wang, Yanfeng; Litvinov, Rustem I.; Chen, Xinsheng
- Journal of Clinical Investigation
CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data
journal, July 2013
- Huang, Jing; MacKerell, Alexander D.
- Journal of Computational Chemistry, Vol. 34, Issue 25
Inositol 1,3,4,5,6-pentakisphosphate 2-kinase is a distant IPK member with a singular inositide binding site for axial 2-OH recognition
journal, May 2010
- Gonzalez, B.; Banos-Sanz, J. I.; Villate, M.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 21
Loss of PIP5KI demonstrates that PIP5KI isoform-specific PIP2 synthesis is required for IP3 formation
journal, September 2008
- Wang, Y.; Chen, X.; Lian, L.
- Proceedings of the National Academy of Sciences, Vol. 105, Issue 37
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
journal, July 1983
- Brooks, Bernard R.; Bruccoleri, Robert E.; Olafson, Barry D.
- Journal of Computational Chemistry, Vol. 4, Issue 2
Role of the Glycine Triad in the ATP-binding Site of cAMP-dependent Protein Kinase
journal, July 1997
- Hemmer, Wolfram; McGlone, Maria; Tsigelny, Igor
- Journal of Biological Chemistry, Vol. 272, Issue 27
PIP2 signaling, an integrator of cell polarity and vesicle trafficking in directionally migrating cells
journal, September 2012
- Thapa, Narendra; Anderson, Richard A.
- Cell Adhesion & Migration, Vol. 6, Issue 5
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Structure of a Human Inositol 1,4,5-Trisphosphate 3-Kinase
journal, September 2004
- González, Beatriz; Schell, Michael J.; Letcher, Andrew J.
- Molecular Cell, Vol. 15, Issue 5
The glycine-rich sequence of protein kinases: a multifunctional element
journal, May 1994
- Bossemeyer, Dirk
- Trends in Biochemical Sciences, Vol. 19, Issue 5
The activation loop of PIP5K functions as a membrane sensor essential for lipid substrate processing
journal, November 2016
- Liu, Aizhuo; Sui, Dexin; Wu, Dianqing
- Science Advances, Vol. 2, Issue 11
2.2 Å refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor
journal, May 1993
- Zheng, J.; Trafny, E. A.; Knighton, D. R.
- Acta Crystallographica Section D Biological Crystallography, Vol. 49, Issue 3
PIP5KI is required for cardiovascular and neuronal development
journal, July 2007
- Wang, Y.; Lian, L.; Golden, J. A.
- Proceedings of the National Academy of Sciences, Vol. 104, Issue 28
Mechanism of substrate specificity of phosphatidylinositol phosphate kinases
journal, July 2016
- Muftuoglu, Yagmur; Xue, Yi; Gao, Xiang
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 31
Lethal Contractural Syndrome Type 3 (LCCS3) Is Caused by a Mutation in PIP5K1C, Which Encodes PIPKIγ of the Phophatidylinsitol Pathway
journal, September 2007
- Narkis, Ginat; Ofir, Rivka; Landau, Daniella
- The American Journal of Human Genetics, Vol. 81, Issue 3
CHARMM: The biomolecular simulation program
journal, July 2009
- Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.
- Journal of Computational Chemistry, Vol. 30, Issue 10
Phosphoinositides in cell regulation and membrane dynamics
journal, October 2006
- Di Paolo, Gilbert; De Camilli, Pietro
- Nature, Vol. 443, Issue 7112
[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997
- Otwinowski, Zbyszek; Minor, Wladek
- Macromolecular Crystallography Part A, 307-326
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories
journal, October 2015
- McGibbon, Robert T.; Beauchamp, Kyle A.; Harrigan, Matthew P.
- Biophysical Journal, Vol. 109, Issue 8
Crystal structure of a transition state mimic of the catalytic subunit of cAMP-dependent protein kinase
journal, March 2002
- Madhusudan, ; Akamine, Pearl; Xuong, Nguyen-Huu
- Nature Structural Biology, Vol. 9, Issue 4
Phosphatidylinositol Phosphate Kinases, a Multifaceted Family of Signaling Enzymes
journal, April 1999
- Anderson, Richard A.; Boronenkov, Igor V.; Doughman, Scott D.
- Journal of Biological Chemistry, Vol. 274, Issue 15
OpenMM 7: Rapid development of high performance algorithms for molecular dynamics
journal, July 2017
- Eastman, Peter; Swails, Jason; Chodera, John D.
- PLOS Computational Biology, Vol. 13, Issue 7
The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis
journal, January 2016
- Sumita, Kazutaka; Lo, Yu-Hua; Takeuchi, Koh
- Molecular Cell, Vol. 61, Issue 2
VMD: Visual molecular dynamics
journal, February 1996
- Humphrey, William; Dalke, Andrew; Schulten, Klaus
- Journal of Molecular Graphics, Vol. 14, Issue 1
Works referencing / citing this record:
Carbohydrate Kinases: A Conserved Mechanism Across Differing Folds
journal, January 2019
- Roy, Sumita; Vivoli Vega, Mirella; Harmer, Nicholas J.
- Catalysts, Vol. 9, Issue 1