HSP70-binding motifs function as protein quality control degrons
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HSP70-binding motifs function as protein quality control degrons. / Abildgaard, Amanda B.; Voutsinos, Vasileios; Petersen, Søren D.; Larsen, Fia B.; Kampmeyer, Caroline; Johansson, Kristoffer E.; Stein, Amelie; Ravid, Tommer; Andréasson, Claes; Jensen, Michael K.; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.
I: Cellular and Molecular Life Sciences, Bind 80, Nr. 1, 32, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - HSP70-binding motifs function as protein quality control degrons
AU - Abildgaard, Amanda B.
AU - Voutsinos, Vasileios
AU - Petersen, Søren D.
AU - Larsen, Fia B.
AU - Kampmeyer, Caroline
AU - Johansson, Kristoffer E.
AU - Stein, Amelie
AU - Ravid, Tommer
AU - Andréasson, Claes
AU - Jensen, Michael K.
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
N1 - Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2023
Y1 - 2023
N2 - Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.
AB - Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.
KW - Chaperone
KW - Proteasome
KW - Protein degradation
KW - Protein quality control
KW - Protein stability
KW - Protein unfolding
U2 - 10.1007/s00018-022-04679-3
DO - 10.1007/s00018-022-04679-3
M3 - Journal article
C2 - 36609589
AN - SCOPUS:85145698548
VL - 80
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
SN - 1420-682X
IS - 1
M1 - 32
ER -
ID: 332934051