Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria

Human Mutation
Tanja PlesslD Sean Froese

Abstract

Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations. We biochemically investigated how missense mutations in MMAA in 22 patients lead to disease. About a third confer instability to the recombinant protein in bacterial and human expression systems. All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding. However, all mutations strongly decreased functional association with MUT by reducing GTPase activity stimulation upon incubation with MUT, while nine mutant proteins additionally lost the ability to physically bind MUT. Finally, all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT. This work...Continue Reading

References

Aug 14, 1975·The New England Journal of Medicine·M G AmpolaK Tanaka
Aug 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·R A GravelL E Rosenberg
Apr 14, 1983·The New England Journal of Medicine·S M MatsuiL E Rosenberg
Feb 22, 2001·The Journal of Clinical Investigation·M R BaumgartnerD Valle
Nov 10, 2001·Science·I R Vetter, A Wittinghofer
Mar 28, 2002·Journal of Molecular Biology·Detlef D LeipeL Aravind
Nov 20, 2002·Proceedings of the National Academy of Sciences of the United States of America·C Melissa DobsonRoy A Gravel
Feb 13, 2003·Current Opinion in Structural Biology·Christian Herrmann
Jan 22, 2004·The Journal of Biological Chemistry·Natalia Korotkova, Mary E Lidstrom
Aug 5, 2004·The Journal of Biological Chemistry·Terttu SuormalaBrian Fowler
Sep 7, 2004·The Journal of Biological Chemistry·Nicole A LealThomas A Bobik
Nov 4, 2004·Human Mutation·Jordan P Lerner-EllisDavid S Rosenblatt
Mar 23, 2005·Molecular Genetics and Metabolism·Maria Angeles MartínezBelén Pérez
Apr 28, 2006·The Journal of Biological Chemistry·Dominique PadovaniRuma Banerjee
Jul 27, 2006·Biochemistry·Dominique Padovani, Ruma Banerjee
Jun 29, 2007·Pediatric Research·Friederike HörsterE Regula Baumgartner
Aug 31, 2007·The Journal of Biological Chemistry·Paul A HubbardCatherine L Drennan
Feb 12, 2008·Nature Chemical Biology·Dominique PadovaniRuma Banerjee
Jun 20, 2008·Journal of Inherited Metabolic Disease·B FowlerM R Baumgartner
Dec 4, 2009·Proceedings of the National Academy of Sciences of the United States of America·Dominique Padovani, Ruma Banerjee
May 11, 2011·Genetics in Medicine : Official Journal of the American College of Medical Genetics·John J MitchellCharles R Scriver
Jul 20, 2011·Nature Chemical Biology·Jacqueline Cherfils, Mahel Zeghouf
Jun 15, 2012·Molecular Genetics and Metabolism·Nithiwat VatanavicharnPornswan Wasant
Oct 3, 2012·Molecular Genetics and Metabolism·Laura Dempsey-NunezDavid S Rosenblatt
Jul 23, 2013·Nature Chemical Biology·Michael LofgrenRuma Banerjee
Sep 3, 2013·The Journal of Biological Chemistry·Michael LofgrenRuma Banerjee
Sep 26, 2013·Orphanet Journal of Rare Diseases·Mathilde NizonPascale de Lonlay
Oct 18, 2014·Nature Reviews. Drug Discovery·Adrienne D CoxChanning J Der
Feb 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Marco JostCatherine L Drennan
Jun 11, 2015·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Ljubica CaldovicHiroki Morizono
Oct 21, 2015·The Journal of Biological Chemistry·D Sean FroeseWyatt W Yue
Feb 9, 2016·Nature Communications·Yasmine WhiteAri J Firestone

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Citations

Jun 5, 2018·Intractable & Rare Diseases Research·Xiaoyan ZhouJinxiang Han
Jan 30, 2019·Journal of Inherited Metabolic Disease·D Sean FroeseMatthias R Baumgartner
Mar 7, 2019·Current Topics in Medicinal Chemistry·Ebtesam Al-SuhaimiAbdelhamid Elaissari
Dec 4, 2019·Molecular Genetics & Genomic Medicine·Min ChenSitao Li
Aug 6, 2020·Journal of Inherited Metabolic Disease·Friederike HörsterUNKNOWN Additional Contributors from E-IMD

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