title: The direction of protein entry into the proteasome determines the variety of products and depends on the force needed to unfold its two termini.
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.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dikla
authors.initials: D
authors.lastname: Berko
authors.forename: Shira
authors.initials: S
authors.lastname: Tabachnick-Cherny
authors.forename: Dalit
authors.initials: D
authors.lastname: Shental-Bechor
authors.forename: Paolo
authors.initials: P
authors.lastname: Cascio
authors.forename: Silvia
authors.initials: S
authors.lastname: Mioletti
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Levy
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziv
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: Ami
authors.initials: A
authors.lastname: Navon
mesh_terms: D000818:Animals; D002147:Calmodulin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D002364:Caseins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D058619:Maltose-Binding Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D002364:Caseins; D058619:Maltose-Binding Proteins; D011506:Proteins; D010047:Ovalbumin; D046988:Proteasome Endopeptidase Complex