Degradation of some polyubiquitinated proteins requires an intrinsic proteasomal binding element in the substrates.
Lysine 48-linked polyubiquitin chains usually target proteins for 26 S proteasomal degradation; however, this modification is not a warrant for destruction. Here, we found that efficient degradation of a physiological substrate UbcH10 requires not only an exogenous polyubiquitin chain modification but also its unstructured N-terminal region. Interestingly, the unstructured N-terminal region of UbcH10 directly binds the 19 S regulatory complex of the 26 S proteasome, and it mediates the initiation of substrate translocation. To promote ubiquitin-dependent degradation of the folded domains of UbcH10, its N-terminal region can be displaced by exogenous proteasomal binding elements. Moreover, the unstructured N-terminal region can initiate substrate translocation even when UbcH10 is artificially cyclized without a free terminus. Polyubiquitinated circular UbcH10 is completely degraded by the 26 S proteasome. Accordingly, we propose that degradation of some polyubiquitinated proteins requires two binding interactions: a polyubiquitin chain and an intrinsic proteasomal binding element in the substrates (likely an unstructured region); moreover, the intrinsic proteasomal binding element initiates substrate translocation regardless of its location in the substrates.
Zhao
Minglian
M
Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
Zhang
Nan-Yan
NY
Zurawel
Ashley
A
Hansen
Kirk C
KC
Liu
Chang-Wei
CW
D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D002850:Chromatography, Gel; D002942:Circular Dichroism; D013058:Mass Spectrometry; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D025821:Polyubiquitin; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex