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The endoplasmic reticulum HSP 40 co‐chaperone ER dj3/ DNAJB 11 assembles and functions as a tetramer
Author(s) -
Chen KaiChun,
Qu Song,
Chowdhury Saikat,
Noxon Isabelle C,
Schonhoft Joseph D,
Plate Lars,
Powers Evan T,
Kelly Jeffery W,
Lander Gabriel C,
Wiseman R Luke
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695616
Subject(s) - endoplasmic reticulum , proteostasis , unfolded protein response , chaperone (clinical) , extracellular , biology , calnexin , microbiology and biotechnology , secretion , er retention , protein subunit , biochemistry , calreticulin , pathology , mutant , medicine , gene
ER dj3/ DNAJB 11 is an endoplasmic reticulum ( ER )‐targeted HSP 40 co‐chaperone that performs multifaceted functions involved in coordinating ER and extracellular proteostasis. Here, we show that ER dj3 assembles into a native tetramer that is distinct from the dimeric structure observed for other HSP 40 co‐chaperones. An electron microscopy structural model of full‐length ER dj3 shows that these tetramers are arranged as a dimer of dimers formed by distinct inter‐subunit interactions involving ER dj3 domain II and domain III . Targeted deletion of residues 175‐190 within domain II renders ER dj3 a stable dimer that is folded and efficiently secreted from mammalian cells. This dimeric ER dj3 shows impaired substrate binding both in the ER and extracellular environments and reduced interactions with the ER HSP 70 chaperone BiP. Furthermore, we show that overexpression of dimeric ER dj3 exacerbates ER stress‐dependent reductions in the secretion of a destabilized, aggregation‐prone protein and increases its accumulation as soluble oligomers in extracellular environments. These results reveal ER dj3 tetramerization as an important structural framework for ER dj3 functions involved in coordinating ER and extracellular proteostasis in the presence and absence of ER stress.