Molecular basis for the structural instability of human DJ-1 induced by the L166P mutation associated with Parkinson's disease.

Biochemistry
Peter C Anderson, Valerie Daggett

Abstract

DJ-1 is a dimeric protein of unknown function in vivo. A mutation in the human DJ-1 gene causing substitution of proline for leucine at residue 166 (L166P) has been linked to early onset Parkinson's disease. Lack of structural stability has precluded experimental determination of atomic-resolution structures of the L166P DJ-1 polymorph. We have performed multiple molecular dynamics (MD) simulations ( approximately 1/3 mus) of the wild-type and L166P DJ-1 polymorph at physiological temperature to predict specific structural effects of the L166P substitution. L166P disrupted helices alpha1, alpha5, alpha6 and alpha8 with alpha8 undergoing particularly severe disruption. Secondary structural elements critical for protein stability and dimerization were significantly disrupted across the entire dimer interface, as were extended hydrophobic surfaces involved in dimer formation. Relative to wild-type DJ-1, L166P DJ-1 populated a broader ensemble of structures, many of which corresponded to distorted conformations. In a L166P dimer model the substitution significantly destabilized the dimer interface, interrupting >100 intermolecular contacts that are important for dimer formation. The L166P substitution also led to major perturbation...Continue Reading

References

May 5, 1982·Journal of Molecular Biology·J Kyte, R F Doolittle
Feb 13, 1997·Biochemical and Biophysical Research Communications·D NagakuboH Ariga
Aug 28, 1997·Nature·M G SpillantiniM Goedert
Oct 17, 1998·Nature·E LeroyM H Polymeropoulos
Feb 18, 1999·Journal of Cellular Biochemistry·Y HodM R El-Maghrabi
Jul 31, 2001·The Journal of Biological Chemistry·K TakahashiH Ariga
May 23, 2003·The Journal of Biological Chemistry·Xiao Tao, Liang Tong
Jun 11, 2003·The Journal of Biological Chemistry·Kazuya HonbouFuyuhiko Inagaki
Jul 10, 2003·The Journal of Biological Chemistry·David W MillerMark R Cookson
Jul 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Mark A WilsonGregory A Petsko
Aug 27, 2003·The Journal of Biological Chemistry·Sun-Joo LeeSun-Shin Cha
Nov 11, 2003·The Journal of Biological Chemistry·Karin GörnerPhilipp J Kahle
Dec 11, 2003·The Journal of Biological Chemistry·James A OlzmannLih-Shen Chin
Jan 28, 2004·Proceedings of the National Academy of Sciences of the United States of America·Mark A WilsonGregory A Petsko
Apr 17, 2004·Science·Enza Maria ValenteNicholas W Wood
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Jul 31, 2004·Methods : a Companion to Methods in Enzymology·David A C Beck, Valerie Daggett
Nov 3, 2004·Molecular and Cellular Neurosciences·Stéphanie BaulacWeiming Xia
Mar 16, 2005·Cancer Cell·Raymond H KimTak W Mak
Jun 25, 2005·Cell Death and Differentiation·Y ShinboH Ariga
Jan 13, 2006·Journal of Molecular Biology·Wenbo ZhouAnthony L Fink
Mar 18, 2006·Nature Reviews. Genetics·Matthew James Farrer
Sep 4, 2007·Proceedings of the National Academy of Sciences of the United States of America·Eva Andres-MateosValina L Dawson
Jan 30, 2008·Protein Science : a Publication of the Protein Society·Freddie R SalsburyJacquelyn S Fetrow
Feb 19, 2008·The FEBS Journal·Andrea C Belin, Marie Westerlund
Apr 26, 2008·Protein Science : a Publication of the Protein Society·Gaetano Malgieri, David Eliezer

❮ Previous
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Citations

Nov 28, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Mariaelena RepiciFlaviano Giorgini
Jun 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Carolyn I HallMatthew Bogyo
Nov 26, 2010·The Journal of Biological Chemistry·R Sean McNallyJenny P-Y Ting
Mar 21, 2012·The Journal of Biological Chemistry·Stefania GirottoStefano Mammi
May 11, 2012·Journal of Biomolecular Structure & Dynamics·Calvin Yu-Chian Chen
Feb 9, 2012·Cold Spring Harbor Perspectives in Medicine·Christine Klein, Ana Westenberger
Oct 13, 2010·Journal of Geriatric Psychiatry and Neurology·Lynn M BekrisCyrus P Zabetian
May 13, 2014·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Yoshiyuki Suzuki
Sep 2, 2010·Journal of Neuroscience Research·Chenere P Ramsey, Benoit I Giasson
Jun 21, 2014·The Biochemical Journal·Jun MaZengqiang Yuan
Jun 8, 2011·Neurobiology of Disease·Yukiko UsamiNobutaka Hattori
Apr 20, 2010·Structure·Marc W van der KampValerie Daggett
Jul 15, 2015·The Journal of Biological Chemistry·Søs G MathiassenRasmus Hartmann-Petersen
May 6, 2019·Journal of Bioenergetics and Biomembranes·Ludmila P DolgachevaAndrey Y Abramov
Jun 27, 2021·Progress in Neurobiology·Maoxin Huang, Shengdi Chen
Feb 23, 2019·Journal of Chemical Information and Modeling·Abhishek KumarPriyadarshi Satpati

❮ Previous
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