Structure of a complex between Nedd8 and the Ulp/Senp protease family member Den1.
The Nedd8 conjugation pathway is conserved from yeast to humans and is essential in many organisms. Nedd8 is conjugated to cullin proteins in a process that alters SCF E3 ubiquitin ligase activity, and it is presumed that Nedd8 deconjugation would reverse these effects. We now report the X-ray structures of the human Nedd8-specific protease, Den1, in a complex with the inhibitor Nedd8 aldehyde, thus revealing a model for the tetrahedral transition state intermediate generated during proteolysis. Although Den1 is closely related to the SUMO-specific protease family (Ulp/Senp family), structural analysis of the interface suggests determinants involved in Nedd8 selectivity by Den1 over other ubiquitin-like family members and suggests how the Ulp/Senp architecture has been modified to interact with different ubiquitin-like modifiers.
Reverter
David
D
Structural Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Wu
Kenneth
K
Erdene
Tudeviin Gan
TG
Pan
Zhen-Qiang
ZQ
Wilkinson
Keith D
KD
Lima
Christopher D
CD
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000075687:NEDD8 Protein; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D014452:Ubiquitins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D046911:Macromolecular Substances; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014452:Ubiquitins; D010450:Endopeptidases; C477008:SENP8 protein, human