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70kDa heat shock protein 5 (BiP) ATPase domain in complex with ADP

PDB Code 3IUC Target Class ATPases Target HSPA5 Alias BIP, FLJ26106, GRP78, HSPA5, MIF2 Disease Area/Function cancer Date Deposited Aug 31 2009 Authors Wisniewska, M. Karlberg, T. Arrowsmith, C.H. Berglund, H. Bountra, C. Collins, R. Edwards, A.M. Flodin, S. Flores, A. Graslund, S. Hammarstrom, M. Johansson, A. Johansson, I. Kallas, A. Kraulis, P. Kotenyova, T. Kotzsch, A. Markova, N. Moche, M. Nielsen, T.K. Nordlund, P. Nyman, T. Persson, C. Roos, A.K. Siponen, M.I. Schutz, P. Svensson, L. Thorsell, A.G. Tresaugues, L. Van Den Berg, S. Wahlberg, E. Weigelt, J. Welin, M. Schuler, H.

About this structure

Human heat shock-70 protein-5 (HSPA5/BiP/GRP78; refs. 1,2) is the most abundant member of the Hsp70 protein family in the ER lumen. HSPA5 was originally termed immunoglobulin heavy chain binding protein (BiP), and is now known to have a crucial role in the assembly of ER proteins and protein complexes and the unfolded protein response (3). Both HSPA5 and its interaction partners are linked to a number of diseases including infectious diseases, inherited diseases, and several types of cancer (4-6).

We have previously determined crystal structures of the ATPase domains of HSPA6 (PDB: 3fe1), HSPA1L (3gdq) and HSPA2 (3i33). Here, the structure of the ATPase domain of HSPA5 (residues D26 – D410) resolution was solved and refined to 2.4 Å. Our structure reveals the protein with ADP and metal ion bound in the cleft between the two major lobes of the ATPase domain. No density for inorganic phosphate was observed. Given the cation coordination geometry and distances, together with the crystallization conditions (200 mM CaCl2), the cation was indicated as calcium.

References

  1. Ting J, Lee ASD (1988) Human gene encoding the 78,000-dalton glucose-regulated protein and its pseudogene: structure, conservation, and regulation. DNA 7: 275-286
  2. Hendershot LM, Valentine VA, Lee AS, Morris SW (1994) Localization of the Gene Encoding Human Bip/Grp78, the Endoplasmic-Reticulum Cognate of the Hsp70 Family, to Chromosome-9q34. Genetics 20, 281-284.
  3. Brewer JW, Hendershot LM (2006) Building an antibody factory: a job for the unfolded protein response. Nature Immunol 6, 23-29
  4. Fu Y, Lee AS (2006) Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther 5, 741-744
  5. Dong DZ et al (2008) Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor anglogenesis in transgene-induced mammary tumor development. Cancer Res. 68, 498-505
  6. Dudek J, Benedix J, Cappel S, Greiner M, Jalal C, Müller L, Zimmermann R (2009) Function and pathologies of BiP and its interaction partners. Cell. Mol. Life Sci. 66, 1556-1569