title: Structural determinants of MALT1 protease activity.
abstract: The formation of the CBM (CARD11-BCL10-MALT1) complex is pivotal for antigen-receptor-mediated activation of the transcription factor NF-κB. Signaling is dependent on MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), which not only acts as a scaffolding protein but also possesses proteolytic activity mediated by its caspase-like domain. It remained unclear how the CBM activates MALT1. Here, we provide biochemical and structural evidence that MALT1 activation is dependent on its dimerization and show that mutations at the dimer interface abrogate activity in cells. The unliganded protease presents itself in a dimeric yet inactive state and undergoes substantial conformational changes upon substrate binding. These structural changes also affect the conformation of the C-terminal Ig-like domain, a domain that is required for MALT1 activity. Binding to the active site is coupled to a relative movement of caspase and Ig-like domains. MALT1 binding partners thus may have the potential of tuning MALT1 protease activity without binding directly to the caspase domain.
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4002 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Lukas
authors.initials: L
authors.lastname: Leder
authors.forename: Jutta
authors.initials: J
authors.lastname: Blank
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.forename: Samu
authors.initials: S
authors.lastname: Melkko
authors.forename: Arnaud
authors.initials: A
authors.lastname: Decock
authors.forename: Allan
authors.initials: A
authors.lastname: D'Arcy
authors.forename: Frederic
authors.initials: F
authors.lastname: Villard
authors.forename: Paulus
authors.initials: P
authors.lastname: Erbel
authors.forename: Nicola
authors.initials: N
authors.lastname: Hughes
authors.forename: Felix
authors.initials: F
authors.lastname: Freuler
authors.forename: Rainer
authors.initials: R
authors.lastname: Nikolay
authors.forename: Juliano
authors.initials: J
authors.lastname: Alves
authors.forename: Frederic
authors.initials: F
authors.lastname: Bornancin
authors.forename: Martin
authors.initials: M
authors.lastname: Renatus
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D002478:Cells, Cultured; D019281:Dimerization; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D008024:Ligands; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011946:Receptors, Antigen; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein