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Mechanisms of protein quality control degradation in the nucleus
Author(s) -
Gardner Richard,
Fredrickson Eric,
Rosenbaum Joel,
Gallagher Pamela
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.86.2
Subject(s) - proteasome , protein folding , chemistry , ubiquitin ligase , folding (dsp implementation) , microbiology and biotechnology , ubiquitin , biophysics , degradation (telecommunications) , protein degradation , proteolysis , aggresome , biochemistry , computational biology , biology , enzyme , computer science , engineering , telecommunications , electrical engineering , gene
Protein quality control (PQC) degradation systems protect the cell from the toxic accumulation of aggregation‐prone misfolded proteins. Because any protein can become misfolded, these systems must be able to distinguish abnormal proteins from normal ones, yet be capable of recognizing the wide variety of distinctly shaped misfolded proteins they are likely to encounter. How individual PQC degradation systems accomplish this remains an open question. In yeast, the nuclear PQC ubiquitin ligase San1 ubiquitinates misfolded nuclear proteins for proteasome degradation. Recently, we found that San1 directly recognizes its misfolded substrates via intrinsically disordered N‐ and C‐terminal domains. These disordered domains are punctuated with small segments of order and high sequence conservation that serve as substrate‐recognition sites San1 uses to target its different substrates. Within its misfolded substrates, San1 requires the exposure of a particular window of hydrophobicity and threshold of insolubility. While other cellular PQC degradation systems require chaperones for substrate degradation, chaperones are only required for San1‐mediated degradation if the misfolded substrate crosses an even higher threshold of insolubility required for San1 recognition. Altogether, our latest results shed new insights into how misfolded proteins are targeted for degradation in the nucleus