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Elife. 2015 Oct 16;4:e08961. doi: 10.7554/eLife.08961.

Physiological modulation of BiP activity by trans-protomer engagement of the interdomain linker.

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Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Department of Biology and Biotechnology, Charles Darwin, Sapienza University of Rome, Rome, Italy.
Laboratorio de Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, United States.
Wellcome Trust-MRC Institute of Metabolic Science, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.


DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis and crosslinking were used to probe the architecture of oligomers formed by the endoplasmic reticulum (ER) Hsp70, BiP. These were found to consist of adjacent protomers engaging the interdomain linker of one molecule in the substrate binding site of another, attenuating the chaperone function of oligomeric BiP. Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between the burden of unfolded proteins and BiP oligomers and slower equilibration between oligomers and inactive, covalently-modified BiP. Lumenal ER calcium depletion caused rapid oligomerization of mammalian BiP and a coincidental diminution in substrate binding, pointing to the relative inertness of the oligomers. Thus, equilibration between inactive oligomers and active monomeric BiP is poised to buffer fluctuations in ER unfolded protein load on a rapid timescale attainable neither by inter-conversion of active and covalently-modified BiP nor by the conventional unfolded protein response.


BiP/GRP78; Hsp70; biochemistry; cell biology; endoplasmic reticulum; none; oligomerization

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