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Minimal length requirement for proteasomal degradation of ubiquitin-dependent substrates

Lisette G. G. C. Verhoef^*,1, Christian Heinen^*, Alexandra Selivanova, Els F. Halff^*, Florian A. Salomons^* and Nico P. Dantuma^*,2

^* Department of Cell and Molecular Biology, The Medical Nobel Institute, and

Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

² Correspondence: Department of Cell and Molecular Biology, The Medical Nobel Institute, Karolinska Institutet, Von Eulers väg 3, S-17177 Stockholm, Sweden. E-mail: nico.dantuma{at}ki.se

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 inhibitory 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.

Key Words: ubiquitin fusion degradation • UBB⁺¹ • neurodegeneration • conformational diseases • Alzheimer • protein degradation

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