2. Academic Validation
  3. Bap (Sil1) regulates the molecular chaperone BiP by coupling release of nucleotide and substrate

Bap (Sil1) regulates the molecular chaperone BiP by coupling release of nucleotide and substrate

  • Nat Struct Mol Biol. 2018 Jan;25(1):90-100. doi: 10.1038/s41594-017-0012-6.
Mathias Rosam 1,  Daniela Krader 2,  Christina Nickels 1,  Janine Hochmair 1,  Katrin C Back 1,  Ganesh Agam 2,  Anders Barth 2,  Cathleen Zeymer 3,  Jelle Hendrix 2 4,  Markus Schneider 5,  Iris Antes 5,  Jochen Reinstein 3,  Don C Lamb 6,  Johannes Buchner 7
Affiliations

Affiliations

  • 1 Center for Integrated Protein Science Munich at the Department of Chemistry, Technical University of Munich, Garching, Germany.
  • 2 Physical Chemistry, Department of Chemistry, Munich Center for Integrated Protein Science, Nanosystems Initiative Munich and Center for Nanoscience, Ludwig Maximilians University of Munich, Munich, Germany.
  • 3 Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Heidelberg, Germany.
  • 4 Faculty of Medicine and Life Sciences and Biomedical Research Institute, Hasselt University, Hasselt, Belgium.
  • 5 Center for Integrated Protein Science Munich at the Wissenschaftszentrum Weihenstephan, Technical University of Munich, Weihenstephan, Germany.
  • 6 Physical Chemistry, Department of Chemistry, Munich Center for Integrated Protein Science, Nanosystems Initiative Munich and Center for Nanoscience, Ludwig Maximilians University of Munich, Munich, Germany. [email protected].
  • 7 Center for Integrated Protein Science Munich at the Department of Chemistry, Technical University of Munich, Garching, Germany. [email protected].
PMID: 29323281 DOI: 10.1038/s41594-017-0012-6
Abstract

BiP is the endoplasmic member of the HSP70 family. BiP is regulated by several co-chaperones including the nucleotide-exchange factor (NEF) Bap (Sil1 in yeast). Bap is a two-domain protein. The interaction of the Bap C-terminal domain with the BiP ATPase domain is sufficient for its weak NEF activity. However, stimulation of the BiP ATPase activity requires full-length Bap, suggesting a complex interplay of these two factors. Here, single-molecule FRET experiments with mammalian proteins reveal that Bap affects the conformation of both BiP domains, including the lid subdomain, which is important for substrate binding. The largely unstructured Bap N-terminal domain promotes the substrate release from BiP. Thus, Bap is a conformational regulator affecting both nucleotide and substrate interactions. The preferential interaction with BiP in its ADP state places Bap at a late stage of the chaperone cycle, in which it coordinates release of substrate and ADP, thereby resetting BiP for ATP and substrate binding.

Figures
Products