The Direction of Protein Entry into the Proteasome Determines the Variety of Products and Depends on the Force Needed to Unfold Its Two Termini

Dikla Berko, Shira Tabachnick-Cherny, Dalit Shental-Bechor, Paolo Cascio, Silvia Mioletti, Yaakov Levy, Arie Admon, Tamar Ziv, Boaz Tirosh, Alfred L. Goldberg, Ami Navon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Poorly structured domains in proteins enhance their susceptibility to proteasomal degradation. To learn whether the presence of such a domain near either end of a protein determines its direction of entry into the proteasome, directional translocation was enforced on several proteasome substrates. Using archaeal PAN-20S complexes, mammalian 26S proteasomes, and cultured cells, we identified proteins that are degraded exclusively from either the C or N terminus and some showing no directional preference. This property results from interactions of the substrate's termini with the regulatory ATPase and could be predicted based on the calculated relative stabilities of the N and C termini. Surprisingly, the direction of entry into the proteasome affected markedly the spectrum of peptides released and consequently influenced the efficiency of MHC class I presentation. Thus, easily unfolded termini are translocated first, and the direction of translocation influences the peptides generated and presented to the immune system.

Original languageAmerican English
Pages (from-to)601-611
Number of pages11
JournalMolecular Cell
Volume48
Issue number4
DOIs
StatePublished - 30 Nov 2012

Bibliographical note

Funding Information:
A.N. is an incumbent of the Recanati career development chair of cancer research. Research in the laboratory of A.N. is supported by the Israel Science Foundation (ISF), the Minerva Foundation (Germany), the German-Israeli Foundation for Scientific Research and Development (GIF), and a special gift from Rolando Uziel. These studies were also supported in part by a grant to A.L.G. from the NIH (GM05 1923-10).

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