The structure of TAX1BP1 UBZ1+2 provides insight into target specificity and adaptability.
TAX1BP1 is a novel ubiquitin-binding adaptor protein involved in the negative regulation of the NF-kappaB transcription factor, which is a key player in inflammatory responses, immunity and tumorigenesis. TAX1BP1 recruits A20 to the ubiquitinated signaling proteins TRAF6 and RIP1, leading to their A20-mediated deubiquitination and the disruption of IL-1-induced and TNF-induced NF-kappaB signaling, respectively. The two zinc fingers localized at its C-terminus function as novel ubiquitin-binding domains (UBZ, ubiquitin-binding zinc finger). Here we present for the first time both the solution and crystal structures of two classical UBZ domains in tandem within the human TAX1BP1. The relative orientation of the two domains is slightly different in the X-ray structure with respect to the NMR structure, indicating some degree of conformational flexibility, which is rationalized by NMR relaxation data. The observed degree of flexibility and stability between the two UBZ domains might have consequences on the recognition mechanism of interacting partners.
Departamento de Química Física e Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, Granada 18071, Spain; Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels 1050, Belgium; Molecular Recognition Unit, Department of Structural Biology, VIB, Brussels 1050, Belgium.
M Angeles
MA
Ceregido
Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas, Valencia 46010, Spain; Departamento de Biología Físico-Química, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid 28040, Spain.
Mercedes
M
Spínola Amilibia
Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels 1050, Belgium; Molecular Recognition Unit, Department of Structural Biology, VIB, Brussels 1050, Belgium.
Lieven
L
Buts
Department of Epidemiology, Atherothrombosis and Imaging, Spanish National Cardiovascular Research Center, Madrid 28029, Spain.
José
J
Rivera-Torres
Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels 1050, Belgium; Molecular Recognition Unit, Department of Structural Biology, VIB, Brussels 1050, Belgium.
Abel
A
Garcia-Pino
Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientificas, Valencia 46010, Spain. Electronic address: jbravo@ibv.csic.es.
Jerónimo
J
Bravo
Jean Jeener NMR Centre, Structural Biology Brussels, Vrije Universiteit Brussel, Brussels 1050, Belgium; Molecular Recognition Unit, Department of Structural Biology, VIB, Brussels 1050, Belgium. Electronic address: nvnuland@vub.ac.be.
Nico A J
NA
van Nuland
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C120635:TAX1BP1 protein, human; D025801:Ubiquitin
2D; 3D; NMR; NOE; SAXS; X-ray; hetNOE; heteronuclear NOE; inflammation; nuclear Overhauser enhancement; small-angle X-ray scattering; three-dimensional; two-dimensional; ubiquitin-binding domains