The mechanism of Z alpha 1-antitrypsin accumulation in the liver

Nature
D A LomasR W Carrell

Abstract

Most northern Europeans have only the normal M form of the plasma protease inhibitor alpha 1-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant. For reasons that have not been well-understood, the Z mutation results in a blockage in the final stage of processing of antitrypsin in the liver such that in the Z homozygote only 15% of the protein is secreted into the plasma. The 85% of the alpha 1-antitrypsin that is not secreted accumulates in the endoplasmic reticulum of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. These inclusions are associated with hepatocellular damage, and 10% of newborn Z homozygotes develop liver disease which often leads to a fatal childhood cirrhosis. Here we demonstrate the molecular pathology underlying this accumulation and describe how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive centre loop of one molecule and the gap in the A-sheet of another. This loop-sheet polymerization of Z antitrypsin occurs spontaneously at 37 degrees C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. Z antitrypsin polymerized in ...Continue Reading

References

Sep 1, 1975·European Journal of Biochemistry·C B LaurellE Thulin
Sep 20, 1991·Journal of Molecular Biology·P Stein, C Chothia
Oct 10, 1991·Nature·R W CarrellP E Stein
Nov 26, 1990·European Journal of Biochemistry·A J SchulzeC B Laurell
Apr 1, 1989·The Journal of Clinical Investigation·J A CarlsonS L Woo
Dec 1, 1986·The Journal of Clinical Investigation·R W Carrell

❮ Previous
Next ❯

Citations

Jun 1, 1996·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·H T Wright
Sep 1, 1993·Protein Science : a Publication of the Protein Society·T Samandari, J L Brown
Nov 1, 1996·Protein Science : a Publication of the Protein Society·H KoloczekJ Potempa
Jan 1, 1997·Protein Science : a Publication of the Protein Society·W S ChangM R Wardell
Jul 31, 1998·Protein Science : a Publication of the Protein Society·S D Betts, J King
Feb 22, 2012·Archivum Immunologiae Et Therapiae Experimentalis·David A BerginEmer P Reeves
Nov 4, 2005·Springer Seminars in Immunopathology·Marco CicardiBenedetta Cicardi
Nov 15, 2011·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Gillian L McNabRobert A Stockley
Jun 15, 2007·Lung·Alan T MulgrewN Gerry McElvaney
Dec 14, 2007·Histochemistry and Cell Biology·Jürgen RothChristian Zuber
Feb 23, 2011·Molecules and Cells·Jürgen RothJin Won Cho
Apr 11, 2009·Apoptosis : an International Journal on Programmed Cell Death·Vanya I Rasheva, Pedro M Domingos
Jan 15, 2008·Journal of Inherited Metabolic Disease·C M GreeneN G McElvaney
Mar 3, 2006·Current Gastroenterology Reports·Jeffrey H Teckman, Douglas Lindblad
Nov 24, 2011·Biomolecular NMR Assignments·Mun Peak NyonBibek Gooptu
Jun 19, 2013·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Alice M Turner
Nov 29, 1994·Biochimica Et Biophysica Acta·C G Llewellyn-JonesR A Stockley
Aug 1, 1995·Current Opinion in Cell Biology·C Hammond, A Helenius
Aug 1, 1992·Current Opinion in Biotechnology·D C CrowtherR W Carrell
Dec 4, 2002·Journal of Molecular Biology·Glyn L DevlinStephen P Bottomley
Dec 25, 2002·Journal of Molecular Biology·Dimitri GilisStephen P Bottomley
Jul 12, 1997·Lancet·R W Carrell, D A Lomas
Feb 19, 1999·Biochimica Et Biophysica Acta·M C GaillardD A Lomas
Dec 29, 2000·Journal of Hepatology·H P FischerH Zhou
Oct 27, 1998·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·P RobsonF W Keeley
Jan 23, 1999·Current Opinion in Structural Biology·R W Carrell, B Gooptu
Oct 9, 2001·Trends in Biochemical Sciences·C M CabralR N Sifers
Dec 31, 2003·Methods : a Companion to Methods in Enzymology·Timothy R DaffornStephen P Bottomley
Apr 4, 2003·The International Journal of Biochemistry & Cell Biology·Helen ParfreyDavid A Lomas
Apr 5, 2003·Best Practice & Research. Clinical Gastroenterology·Mark E Mailliard, John L Gollan
Jul 25, 2009·Biochemistry·Tanusree SenguptaPatrick L Wintrode
Jan 18, 2012·Immunology and Cell Biology·Sumaira Z HasnainMichael A McGuckin
Jan 19, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Christian MuellerTerence R Flotte
Feb 1, 1995·Nature Structural Biology·P E Stein, R W Carrell
May 1, 1995·Nature Structural Biology·R N Sifers
Aug 1, 1996·Nature Structural Biology·P R ElliottJ P Abrahams

❮ Previous
Next ❯

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