title: Monoubiquitination and activity of the paracaspase MALT1 requires glutamate 549 in the dimerization interface.
abstract: The mucosa-associated lymphoid tissue protein-1 (MALT1, also known as paracaspase) is a protease whose activity is essential for the activation of lymphocytes and the growth of cells derived from human diffuse large B-cell lymphomas of the activated B-cell subtype (ABC DLBCL). Crystallographic approaches have shown that MALT1 can form dimers via its protease domain, but why dimerization is relevant for the biological activity of MALT1 remains largely unknown. Using a molecular modeling approach, we predicted Glu 549 (E549) to be localized within the MALT1 dimer interface and thus potentially relevant. Experimental mutation of this residue into alanine (E549A) led to a complete impairment of MALT1 proteolytic activity. This correlated with an impaired capacity of the mutant to form dimers of the protease domain in vitro, and a reduced capacity to promote NF-κB activation and transcription of the growth-promoting cytokine interleukin-2 in antigen receptor-stimulated lymphocytes. Moreover, this mutant could not rescue the growth of ABC DLBCL cell lines upon MALT1 silencing. Interestingly, the MALT1 mutant E549A was unable to undergo monoubiquitination, which we identified previously as a critical step in MALT1 activation. Collectively, these findings suggest a model in which E549 at the dimerization interface is required for the formation of the enzymatically active, monoubiquitinated form of MALT1.
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Katrin
authors: K
authors: Cabalzar
authors: Christiane
authors: C
authors: Pelzer
authors: Annette
authors: A
authors: Wolf
authors: Georg
authors: G
authors: Lenz
authors: Justyna
authors: J
authors: Iwaszkiewicz
authors: Vincent
authors: V
authors: Zoete
authors: Stephan
authors: S
authors: Hailfinger
authors: Margot
authors: M
authors: Thome
mesh_terms: D019943:Amino Acid Substitution; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D018698:Glutamic Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008958:Models, Molecular; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D054875:Ubiquitination
chemical_list: D009363:Neoplasm Proteins; D018698:Glutamic Acid; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
references: Science. 1988 Oct 28;242(4878):540-6
references: 3140380
references: Mol Cell. 2003 Feb;11(2):529-41
references: 12620239
references: J Mol Biol. 2012 May 25;419(1-2):4-21
references: 22366302
references: J Comput Chem. 2009 Jul 30;30(10):1545-614
references: 19444816
references: Cell Cycle. 2011 Aug 1;10(15):2485-96
references: 21750409
references: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14596-601
references: 21873235
references: Curr Opin Cell Biol. 2003 Dec;15(6):725-31
references: 14644197
references: Science. 2011 Jan 28;331(6016):468-72
references: 21273489
references: Biol Chem. 2004 Nov;385(11):1093-8
references: 15576331
references: EMBO J. 2011 May 4;30(9):1742-52
references: 21448133
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: PLoS Biol. 2005 Jun;3(6):e183
references: 15941357
references: J Exp Med. 2009 Oct 26;206(11):2313-20
references: 19841089
references: Nat Rev Immunol. 2006 Nov;6(11):799-812
references: 17063183
references: Structure. 2009 Mar 11;17(3):438-48
references: 19278658
references: Oncogene. 2001 Dec 6;20(56):8142-7
references: 11781828
references: J Immunol. 2007 Apr 1;178(7):4373-84
references: 17371994
references: Nat Immunol. 2008 Mar;9(3):272-81
references: 18264101
references: Cold Spring Harb Perspect Biol. 2010 Sep;2(9):a003004
references: 20685844
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3023-8
references: 18287044
references: Nat Rev Immunol. 2008 Jul;8(7):495-500
references: 18575460
references: Nat Immunol. 2002 Sep;3(9):836-43
references: 12154360
references: Mol Cell. 2004 May 7;14(3):289-301
references: 15125833
references: J Biol Chem. 2001 Jun 1;276(22):19012-9
references: 11262391
references: Annu Rev Immunol. 2009;27:693-733
references: 19302050
references: Mol Cell. 2000 Oct;6(4):961-7
references: 11090634
references: Nature. 2012 Oct 4;490(7418):116-20
references: 22885699
references: J Mol Biol. 1998 Apr 17;277(5):1141-52
references: 9571028
references: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19946-51
references: 19897720
references: J Biol Chem. 2002 Dec 20;277(51):49776-81
references: 12351639
references: Nat Immunol. 2013 Apr;14(4):337-45
references: 23416615
references: Clin Cancer Res. 2011 Nov 1;17(21):6623-31
references: 21868762
references: Nature. 2009 Jun 4;459(7247):717-21
references: 19412164
references: Biochem J. 2012 Apr 1;443(1):287-95
references: 22309193
references: EMBO J. 2007 Nov 14;26(22):4634-45
references: 17948050
references: J Biol Chem. 2007 Apr 6;282(14):10180-9
references: 17287209
references: Nat Immunol. 2008 Mar;9(3):263-71
references: 18223652
references: Nature. 2010 Jan 7;463(7277):88-92
references: 20054396
references: Bioinformatics. 2009 May 1;25(9):1189-91
references: 19151095
references: Cell. 1995 Jan 27;80(2):331-40
references: 7834753
references: Nature. 2006 May 4;441(7089):106-10
references: 16572121
references: J Immunol. 1996 Nov 1;157(9):3974-9
references: 8892630
references: Proteins. 2009;77 Suppl 9:128-32
references: 19626712
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21004-9
references: 22158899
references: Protein Expr Purif. 2012 Aug;84(2):236-46
references: 22683476
references: Science. 2008 Mar 21;319(5870):1676-9
references: 18323416
references: Nat Immunol. 2002 Sep;3(9):830-5
references: 12154356
references: Nat Rev Immunol. 2002 Oct;2(10):725-34
references: 12360211
references: Cancer Cell. 2012 Dec 11;22(6):812-24
references: 23238016
references: J Biol Chem. 2003 May 30;278(22):19852-60
references: 12657634
references: Cancer Cell. 2007 Aug;12(2):115-30
references: 17692804
references: Cancer Cell. 2012 Dec 11;22(6):825-37
references: 23238017
references: Curr Protoc Bioinformatics. 2006 Oct;Chapter 5:Unit-5.6
references: 18428767