A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome.
The proteasome usually completely degrades its target proteins, but it can also degrade a handful of proteins in a limited and site-specific manner. The molecular mechanism for such limited degradation is unknown. The repressor forms of Gli2 and Gli3 transcription factors are generated from their full-length proteins through limited proteasome-mediated protein degradation. In this study, we have taken advantage of the fact that Gli3 is efficiently processed, whereas Gli2 is not, and identified a region of approximately 200 residues in their C termini that determine differential processing of the two proteins. This region, named processing determinant domain, functions as a signal for protein processing in the context of not only Gli2 and Gli3 protein sequences but also a heterologous hybrid protein, which would otherwise be completely degraded by the proteasome. Thus, the processing determinant domain constitutes a novel domain that functions independently. Our findings explain, at the molecular level, why Gli2 and Gli3 are differentially processed and, more importantly, may help understand a probably general mechanism by which the proteasome degrades some of its target proteins partially rather than completely.
Pan
Yong
Y
Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Wang
Baolin
B
D020816:Amino Acid Motifs; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
D000596:Amino Acids; C065683:GLI3 protein, human; C000618551:Gli2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D046988:Proteasome Endopeptidase Complex