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Minimal length requirement for proteasomal degradation of ubiquitin‐dependent substrates
Author(s) -
Verhoef Lisette G. G. C.,
Heinen Christian,
Selivanova Alexandra,
Halff Els F.,
Salomons Florian A.,
Dantuma Nico P.
Publication year - 2009
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/fj.08-115055
Subject(s) - proteasome , ubiquitin , protein degradation , microbiology and biotechnology , degradation (telecommunications) , saccharomyces cerevisiae , chemistry , substrate (aquarium) , biology , biochemistry , gene , telecommunications , ecology , computer science
An erroneous transcriptional process, known as molecular misreading, gives rise to an alternative transcript of the ubiquitin B (UBB) gene. This transcript encodes the protein UBB +1 , which comprises a ubiquitin moiety and a 19‐aa C‐terminal extension. UBB +1 is found in affected neurons in neurodegenerative diseases and behaves as an atypical ubiquitin fusion degradation (UFD) proteasome substrate that is poorly degraded and impedes the ubiquitin/proteasome system. Here, we show that the limited length of UBB +1 is responsible for its inefficient degradation and inhibi‐tory activity. Designed UFD substrates with an equally short 19‐aa or a 20‐aa C‐terminal extension were also poorly degraded and had a general inhibitory activity on the ubiquitin/proteasome system in two unrelated cell lines. Extending the polypeptide to 25 aa sufficed to convert the protein into an efficiently degraded proteasome substrate that lacked inhibitory activity. A similar length dependency was found for degradation of two UFD substrates in Saccharomyces cerevisiae , which suggests that the mechanisms underlying this length constraint are highly conserved. Extending UBB +1 also converted this protein into an efficient substrate of the proteasome. These observations provide an explanation for the accumulation of UBB +1 in neurodegenerative disorders and offers new insights into the physical constraints determining proteasomal degradation.— Verhoef, L. G. G. C., Heinen, C., Selivanova, A., Halff, E. F., Salomons, F. A., Dantuma, N. P. Minimal length requirement for proteasomal degradation of ubiquitin‐dependent substrates. FASEBJ. 23, 123‐133 (2009)