Structures of closed and open conformations of dimeric human ATM

Science Advances
Domagoj BaretićRoger L Williams

Abstract

ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase-related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate-binding site, suggesting that this conformation may represent an inactive or basally active enzyme. The active site is held in this closed conformation by interaction with a long helical hairpin in the TRD3 (tetratricopeptide repeats domain 3) domain of the symmetry-related molecule. The open dimer has two protomers with only a limited contact interface, and it lacks the intermolecular interactions that block the peptide-binding site in the closed dimer. This suggests that the open conformation may be more active. The ATM structure shows the detailed topology of the regulator-interacting N-terminal helical solenoid. The ATM conformational dynamics shown by the structures represent an important step in understanding the enzyme regulation.

References

Dec 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·P V NikolovaA R Fersht
Jan 15, 1999·Human Molecular Genetics·N SandovalD Schindler
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·G C SmithS P Jackson
Jan 5, 2002·Acta Oncologica·M B KastanD Yang
Jan 31, 2003·Nature·Christopher J Bakkenist, Michael B Kastan
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 24, 2004·Journal of Molecular Biology·Richard L WeinbergAlan R Fersht
Jun 21, 2005·Molecular and Cellular Biology·Zhongsheng YouPaul Russell
Sep 6, 2005·Proceedings of the National Academy of Sciences of the United States of America·Yingli SunBrendan D Price
Jul 25, 2006·Journal of Structural Biology·Guang TangSteven J Ludtke
Oct 10, 2007·Molecular and Cellular Biology·Yingli SunBrendan D Price
Jun 4, 2008·Genes & Development·Daniel A MordesDavid Cortez
Jun 11, 2008·Methods in Molecular Biology·Peter H ZwartPaul D Adams
Jul 16, 2008·Molecular and Cellular Biology·Jeffrey J SeidelElizabeth H Blackburn
May 20, 2009·Cell·Jan-Philipp Kruse, Wei Gu
May 26, 2009·DNA Repair·Courtney A Lovejoy, David Cortez
Dec 23, 2009·The Journal of Cell Biology·Sairei SoDavid J Chen
Oct 23, 2010·Science·Zhi GuoTanya T Paull
May 20, 2011·Nucleic Acids Research·Robert D FinnSean R Eddy
Nov 22, 2011·Journal of Molecular Biology·Sjors H W Scheres
Sep 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Michal BistaAlan R Fersht
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
Mar 15, 2013·Nature Reviews. Molecular Cell Biology·Yosef Shiloh, Yael Ziv
May 3, 2013·Nature·Haijuan YangNikola P Pavletich
Nov 12, 2013·Nature Methods·Alp KucukelbirHemant D Tagare
Apr 23, 2014·Nucleic Acids Research·Xavier Robert, Patrice Gouet
Dec 3, 2014·Current Opinion in Structural Biology·Domagoj Baretić, Roger L Williams
Dec 9, 2014·Journal of Structural Biology·Sjors H W Scheres
Dec 31, 2014·Nature Methods·Jianyi YangYang Zhang
Jan 13, 2015·Annual Review of Biochemistry·Tanya T Paull
Apr 18, 2015·Nucleic Acids Research·Alexey DrozdetskiyGeoffrey J Barton
Aug 21, 2015·Protein Expression and Purification·W Mark AbbottDavid Fisher
Nov 26, 2015·Journal of Structural Biology·Kai Zhang
Dec 19, 2015·Science·Christopher H S AylettTimm Maier

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Citations

May 3, 2019·Human Mutation·Alice FiévetMarc-Henri Stern
Dec 23, 2017·Cell Research·Qinhui RaoYanhui Xu
Nov 27, 2019·Biochemical Society Transactions·Alberto Elías-VillalobosDominique Helmlinger
Mar 17, 2020·Annual Review of Biochemistry·David P WatermanMarcus B Smolka
Mar 22, 2018·Nature Communications·Xuejuan WangGang Cai
Jan 2, 2019·Nature Structural & Molecular Biology·Neel H Shah, John Kuriyan
Jan 17, 2019·Biochemical Society Transactions·Tom CeskaPamela A Williams
Jul 20, 2019·Cell Research·Jianxiong XiaoYanhui Xu
Nov 22, 2019·Cellular and Molecular Life Sciences : CMLS·Yueru SunXiaodong Zhang
May 18, 2019·Cell Research·Jiyu XinGang Cai
Oct 4, 2020·Communications Biology·Nash D RochmanEugene V Koonin
Oct 6, 2020·SLAS Discovery·Taiana Maia de OliveiraChris Phillips
Jun 5, 2019·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Xingyi GuoWei Zheng
Jan 14, 2021·The Biochemical Journal·Rashmi Panigrahi, J N Mark Glover
Feb 1, 2020·Pharmacology & Therapeutics·Erik LauriniSabrina Pricl
Sep 24, 2020·Progress in Biophysics and Molecular Biology·Michal HammelJohn A Tainer
Dec 2, 2020·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
Nov 10, 2020·Progress in Biophysics and Molecular Biology·Marijke Jansma, Karl-Peter Hopfner
Oct 22, 2018·International Journal of Radiation Oncology, Biology, Physics·Mira MaaloufNicolas Foray
Apr 23, 2021·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
May 3, 2021·Redox Biology·Arnab PramanickBiswanath Maity
Jun 22, 2021·Critical Reviews in Biochemistry and Molecular Biology·Elias A Tannous, Peter M Burgers
Aug 26, 2021·Nature Reviews. Molecular Cell Biology·Ji-Hoon Lee, Tanya T Paull
Aug 31, 2021·RSC Chemical Biology·Kerry Silva McPherson, Dmitry M Korzhnev
Sep 25, 2021·Nature Structural & Molecular Biology·K StakyteK P Hopfner
Jan 12, 2020·Current Opinion in Structural Biology·Rhys M WilliamsXiaodong Zhang
Nov 12, 2021·Frontiers in Genetics·Sara BiagiottiMauro Magnani

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Methods Mentioned

BETA
electron microscopy
electron cryomicroscopy
light scattering
acetylation
transfection
transfections
size exclusion chromatography
gel filtration
electrophoresis
dynamic light scattering

Software Mentioned

ASTRA
PHENIX
Gautomatch
MotionCorr
Coot
TASSER
EMAN2
RELION
Gctf

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