Structural basis for Ca(2+)-induced activation of human PAD4

Nature Structural & Molecular Biology
Kyouhei AritaMamoru Sato

Abstract

Peptidylarginine deiminase 4 (PAD4) is a Ca(2+)-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. Its gene is a susceptibility locus for rheumatoid arthritis. Here we present the crystal structure of Ca(2+)-free wild-type PAD4, which shows that the polypeptide chain adopts an elongated fold in which the N-terminal domain forms two immunoglobulin-like subdomains, and the C-terminal domain forms an alpha/beta propeller structure. Five Ca(2+)-binding sites, none of which adopt an EF-hand motif, were identified in the structure of a Ca(2+)-bound inactive mutant with and without bound substrate. These structural data indicate that Ca(2+) binding induces conformational changes that generate the active site cleft. Our findings identify a novel mechanism for enzyme activation by Ca(2+) ions, and are important for understanding the mechanism of protein citrullination and for developing PAD-inhibiting drugs for the treatment of rheumatoid arthritis.

References

Mar 1, 1992·Archives of Biochemistry and Biophysics·K Nomura
Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Sep 1, 1993·Journal of Neurochemistry·J W Lamensa, M A Moscarello
Jan 1, 1995·Progress in Biophysics and Molecular Biology·S Jones, J M Thornton
Sep 5, 1993·Journal of Molecular Biology·L Holm, C Sander
Dec 24, 1996·Proceedings of the National Academy of Sciences of the United States of America·H WuW A Hendrickson
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·T C Terwilliger, J Berendzen
Aug 28, 1999·Neuroscience Letters·L B PritzkerM A Moscarello
Oct 26, 1999·Acta Crystallographica. Section D, Biological Crystallography·J W Pflugrath
Mar 25, 2000·The Journal of Investigative Dermatology·A Ishida-YamamotoH Iizuka
Mar 10, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·C Masson-BessièreG Serre
Jul 4, 2001·The Journal of Biological Chemistry·W Cho
Jan 19, 2002·Biochemical and Biophysical Research Communications·Teruki HagiwaraMichiyuki Yamada
Feb 14, 2002·The Journal of Investigative Dermatology·Akemi Ishida-YamamotoHajime Iizuka
Mar 7, 2002·Arthritis Research·Martinus A M van BoekelWalther J van Venrooij
Mar 27, 2002·Nature Structural Biology·Ahmad Khorchid, Mitsuhiko Ikura
Jun 18, 2002·Journal of Neurochemistry·M A MoscarelloD D Wood
Oct 24, 2002·Archives of Biochemistry and Biophysics·Akihito IshigamiNaoki Maruyama
Oct 24, 2002·The Journal of Biological Chemistry·Katsuhiko NakashimaMichiyuki Yamada
Oct 28, 2003·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Erik R VossenaarGer J M Pruijn
Dec 4, 2003·Acta Crystallographica. Section D, Biological Crystallography·Kyouhei AritaMamoru Sato
Jan 1, 2004·The Journal of Biological Chemistry·Andrey GalkinOsnat Herzberg
Jan 1, 1996·Acta Crystallographica. Section D, Biological Crystallography·J P Abrahams, A G Leslie
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Feb 28, 2006·Apoptosis : an International Journal on Programmed Cell Death·G-Y LiuH-C Hung
Aug 22, 2012·Cell Biochemistry and Biophysics·Changsong ZhangLixin Wei
May 15, 2007·Biochemistry·Bryan KnuckleyPaul R Thompson
Feb 21, 2013·Journal of Medicinal Chemistry·Lianhu WeiLakshmi P Kotra
May 16, 2013·Nature Communications·Katsuhiko NakashimaToru Miyazaki
Mar 8, 2007·Nature Reviews. Molecular Cell Biology·Robert J Klose, Yi Zhang
Nov 7, 2007·Nature Structural & Molecular Biology·Sabbi Lall
Nov 1, 2013·Science Translational Medicine·Keith B Elkon
Jul 8, 2009·Molecular and Cellular Biology·Hélène DenisFrançois Fuks
May 29, 2008·Molecular and Cellular Biology·Pingxin LiYanming Wang
Apr 17, 2012·The Journal of Clinical Investigation·Ulrike HarreGeorg Schett
Mar 13, 2010·Cancer Cell International·Xiaotian Chang, Kehua Fang
Jul 3, 2007·Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology·Yasuyoshi NaishiroKohzoh Imai
Mar 29, 2006·Proceedings of the National Academy of Sciences of the United States of America·Kyouhei AritaMamoru Sato
May 21, 2014·Nature Immunology·Kerri A Mowen, Michael David
Mar 7, 2014·Biochimica Et Biophysica Acta·Constance Assohou-LutyGer J M Pruijn
Oct 9, 2013·World Journal of Surgical Oncology·Zhongmin JiangXiaotian Chang
Jun 12, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Masaki UnnoHidenari Takahara
Jan 30, 2010·Cellular and Molecular Life Sciences : CMLS·Marie-Claire MéchinMichel Simon
Oct 17, 2008·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Abdiwahab A MusseGeorge Harauz
Sep 10, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Andrea TrabocchiFabrizio Carta

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