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PDBsum entry 1s3x

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protein ligands metals links
Chaperone PDB id
1s3x
Jmol
Contents
Protein chain
380 a.a. *
Ligands
PO4
ADP
Metals
_CA ×2
_NA ×2
Waters ×408
* Residue conservation analysis
PDB id:
1s3x
Name: Chaperone
Title: The crystal structure of the human hsp70 atpase domain
Structure: Heat shock 70 kda protein 1. Chain: a. Fragment: atpase domain. Synonym: hsp70.1, hsp70-1/hsp70-2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hspa1a, hspa1, hspa1b. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.84Å     R-factor:   0.203     R-free:   0.219
Authors: M.Sriram,J.Osipiuk,B.Freeman,R.I.Morimoto,A.Joachimiak
Key ref:
M.Sriram et al. (1997). Human Hsp70 molecular chaperone binds two calcium ions within the ATPase domain. Structure, 5, 403-414. PubMed id: 9083109 DOI: 10.1016/S0969-2126(97)00197-4
Date:
14-Jan-04     Release date:   20-Jan-04    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P08107  (HSP71_HUMAN) -  Heat shock 70 kDa protein 1A/1B
Seq:
Struc:
 
Seq:
Struc:
641 a.a.
380 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
DOI no: 10.1016/S0969-2126(97)00197-4 Structure 5:403-414 (1997)
PubMed id: 9083109  
 
 
Human Hsp70 molecular chaperone binds two calcium ions within the ATPase domain.
M.Sriram, J.Osipiuk, B.Freeman, R.Morimoto, A.Joachimiak.
 
  ABSTRACT  
 
BACKGROUND: The 70 kDa heat shock proteins (Hsp70) are a family of molecular chaperones, which promote protein folding and participate in many cellular functions. The Hsp70 chaperones are composed of two major domains. The N-terminal ATPase domain binds to and hydrolyzes ATP, whereas the C-terminal domain is required for polypeptide binding. Cooperation of both domains is needed for protein folding. The crystal structure of bovine Hsc70 ATPase domain (bATPase) has been determined and, more recently, the crystal structure of the peptide-binding domain of a related chaperone, DnaK, in complex with peptide substrate has been obtained. The molecular chaperone activity and conformational switch are functionally linked with ATP hydrolysis. A high-resolution structure of the ATPase domain is required to provide an understanding of the mechanism of ATP hydrolysis and how it affects communication between C- and N-terminal domains. RESULTS: The crystal structure of the human Hsp70 ATPase domain (hATPase) has been determined and refined at 1. 84 A, using synchrotron radiation at 120K. Two calcium sites were identified: the first calcium binds within the catalytic pocket, bridging ADP and inorganic phosphate, and the second calcium is tightly coordinated on the protein surface by Glu231, Asp232 and the carbonyl of His227. Overall, the structure of hATPase is similar to bATPase. Differences between them are found in the loops, the sites of amino acid substitution and the calcium-binding sites. Human Hsp70 chaperone is phosphorylated in vitro in the presence of divalent ions, calcium being the most effective. CONCLUSIONS: The structural similarity of hATPase and bATPase and the sequence similarity within the Hsp70 chaperone family suggest a universal mechanism of ATP hydrolysis among all Hsp70 molecular chaperones. Two calcium ions have been found in the hATPase structure. One corresponds to the magnesium site in bATPase and appears to be important for ATP hydrolysis and in vitro phosphorylation. Local changes in protein structure as a result of calcium binding may facilitate phosphorylation. A small, but significant, movement of metal ions and sidechains could position catalytically important threonine residues for phosphorylation. The second calcium site represents a new calcium-binding motif that can play a role in the stabilization of protein structure. We discuss how the information about catalytic events in the active site could be transmitted to the peptide-binding domain.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. Stereo view of the hATPase structure (white ribbon), showing ADP (yellow), sodium ions (yellow spheres), calcium ions (red spheres) and water molecules (blue spheres) bound to the protein.
 
  The above figure is reprinted by permission from Cell Press: Structure (1997, 5, 403-414) copyright 1997.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20012863 A.J.Massey, D.S.Williamson, H.Browne, J.B.Murray, P.Dokurno, T.Shaw, A.T.Macias, Z.Daniels, S.Geoffroy, M.Dopson, P.Lavan, N.Matassova, G.L.Francis, C.J.Graham, R.Parsons, Y.Wang, A.Padfield, M.Comer, M.J.Drysdale, and M.Wood (2010).
A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells.
  Cancer Chemother Pharmacol, 66, 535-545.  
20179333 M.Shida, A.Arakawa, R.Ishii, S.Kishishita, T.Takagi, M.Kukimoto-Niino, S.Sugano, A.Tanaka, M.Shirouzu, and S.Yokoyama (2010).
Direct inter-subdomain interactions switch between the closed and open forms of the Hsp70 nucleotide-binding domain in the nucleotide-free state.
  Acta Crystallogr D Biol Crystallogr, 66, 223-232.
PDB codes: 2e88 2e8a
20072699 M.Wisniewska, T.Karlberg, L.Lehtiö, I.Johansson, T.Kotenyova, M.Moche, and H.Schüler (2010).
Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78.
  PLoS One, 5, e8625.
PDB codes: 3fe1 3gdq 3i33 3iuc 3jxu
20078857 S.Naaby-Hansen, A.Diekman, J.Shetty, C.J.Flickinger, A.Westbrook, and J.C.Herr (2010).
Identification of calcium-binding proteins associated with the human sperm plasma membrane.
  Reprod Biol Endocrinol, 8, 6.  
20111001 T.Kirkegaard, A.G.Roth, N.H.Petersen, A.K.Mahalka, O.D.Olsen, I.Moilanen, A.Zylicz, J.Knudsen, K.Sandhoff, C.Arenz, P.K.Kinnunen, J.Nylandsted, and M.Jäättelä (2010).
Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.
  Nature, 463, 549-553.  
  19908379 Y.Liu, and I.Bahar (2010).
Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones.
  Pac Symp Biocomput, (), 269-280.  
  20862304 Y.Liu, L.M.Gierasch, and I.Bahar (2010).
Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs.
  PLoS Comput Biol, 6, 0.  
18215318 L.Brocchieri, E.Conway de Macario, and A.J.Macario (2008).
hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions.
  BMC Evol Biol, 8, 19.  
18400763 Y.W.Chang, Y.J.Sun, C.Wang, and C.D.Hsiao (2008).
Crystal structures of the 70-kDa heat shock proteins in domain disjoining conformation.
  J Biol Chem, 283, 15502-15511.
PDB codes: 2v7y 2v7z
17647016 H.M.Gunter, and B.M.Degnan (2007).
Developmental expression of Hsp90, Hsp70 and HSF during morphogenesis in the vetigastropod Haliotis asinina.
  Dev Genes Evol, 217, 603-612.  
17923091 Q.Liu, and W.A.Hendrickson (2007).
Insights into Hsp70 chaperone activity from a crystal structure of the yeast Hsp110 Sse1.
  Cell, 131, 106-120.
PDB code: 2qxl
16817317 C.C.Deocaris, S.C.Kaul, and R.Wadhwa (2006).
On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60.
  Cell Stress Chaperones, 11, 116-128.  
16418174 H.K.Lamb, C.Mee, W.Xu, L.Liu, S.Blond, A.Cooper, I.G.Charles, and A.R.Hawkins (2006).
The affinity of a major Ca2+ binding site on GRP78 is differentially enhanced by ADP and ATP.
  J Biol Chem, 281, 8796-8805.  
  16511258 J.Jiang, E.M.Lafer, and R.Sousa (2006).
Crystallization of a functionally intact Hsc70 chaperone.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 39-43.  
16672609 N.R.Buan, K.Rehfeld, and J.C.Escalante-Semerena (2006).
Studies of the CobA-type ATP:Co(I)rrinoid adenosyltransferase enzyme of Methanosarcina mazei strain Go1.
  J Bacteriol, 188, 3543-3550.  
16817320 Y.Lu, Q.Hu, C.Yang, and F.Gao (2006).
Histidine 89 is an essential residue for Hsp70 in the phosphate transfer reaction.
  Cell Stress Chaperones, 11, 148-153.  
17140383 Y.Mao, A.Deng, N.Qu, and X.Wu (2006).
ATPase domain of Hsp70 exhibits intrinsic ATP-ADP exchange activity.
  Biochemistry (Mosc), 71, 1222-1229.  
16307916 J.Jiang, K.Prasad, E.M.Lafer, and R.Sousa (2005).
Structural basis of interdomain communication in the Hsc70 chaperone.
  Mol Cell, 20, 513-524.
PDB code: 1yuw
  16511138 P.C.Aoto, D.T.Ta, J.R.Cupp-Vickery, and L.E.Vickery (2005).
X-ray diffraction analysis of a crystal of HscA from Escherichia coli.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 715-717.  
15666362 V.C.Ruddat, S.Whitman, R.D.Klein, S.M.Fischer, and T.R.Holman (2005).
Evidence for downregulation of calcium signaling proteins in advanced mouse adenocarcinoma.
  Prostate, 64, 128-138.  
15694338 Y.Shomura, Z.Dragovic, H.C.Chang, N.Tzvetkov, J.C.Young, J.L.Brodsky, V.Guerriero, F.U.Hartl, and A.Bracher (2005).
Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange.
  Mol Cell, 17, 367-379.
PDB codes: 1xqr 1xqs
15618627 K.Kawasaki, T.Shibata, and F.Ito (2004).
Roles of the HSP70-subunit in a eukaryotic multi-site-specific endonuclease, Endo.SceI: autophosphorylation and heat stability.
  Biosci Biotechnol Biochem, 68, 2557-2564.  
12918020 J.W.Barclay, and R.M.Robertson (2003).
Role for calcium in heat shock-mediated synaptic thermoprotection in Drosophila larvae.
  J Neurobiol, 56, 360-371.  
12040123 C.S.Sullivan, and J.M.Pipas (2002).
T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis.
  Microbiol Mol Biol Rev, 66, 179-202.  
  12653477 N.Arispe, M.Doh, and A.De Maio (2002).
Lipid interaction differentiates the constitutive and stress-induced heat shock proteins Hsc70 and Hsp70.
  Cell Stress Chaperones, 7, 330-338.  
  11739779 C.Pfund, P.Huang, N.Lopez-Hoyo, and E.A.Craig (2001).
Divergent functional properties of the ribosome-associated molecular chaperone Ssb compared with other Hsp70s.
  Mol Biol Cell, 12, 3773-3782.  
11544208 T.K.Barthel, J.Zhang, and G.C.Walker (2001).
ATPase-defective derivatives of Escherichia coli DnaK that behave differently with respect to ATP-induced conformational change and peptide release.
  J Bacteriol, 183, 5482-5490.  
10745003 M.E.Gottesman, and W.A.Hendrickson (2000).
Protein folding and unfolding by Escherichia coli chaperones and chaperonins.
  Curr Opin Microbiol, 3, 197-202.  
  10585970 A.J.Macario, M.Lange, B.K.Ahring, and E.C.De Macario (1999).
Stress genes and proteins in the archaea.
  Microbiol Mol Biol Rev, 63, 923.  
10612293 F.A.Witzmann, M.D.Bauer, A.M.Fieno, R.A.Grant, T.W.Keough, S.E.Kornguth, M.P.Lacey, F.L.Siegel, Y.Sun, L.S.Wright, R.S.Young, and M.L.Witten (1999).
Proteomic analysis of simulated occupational jet fuel exposure in the lung.
  Electrophoresis, 20, 3659-3669.  
10216320 J.Osipiuk, M.A.Walsh, B.C.Freeman, R.I.Morimoto, and A.Joachimiak (1999).
Structure of a new crystal form of human Hsp70 ATPase domain.
  Acta Crystallogr D Biol Crystallogr, 55, 1105-1107.
PDB code: 1hjo
9705292 A.Schneider, R.W.Smith, A.R.Kautz, K.Weisshart, F.Grosse, and H.P.Nasheuer (1998).
Primase activity of human DNA polymerase alpha-primase. Divalent cations stabilize the enzyme activity of the p48 subunit.
  J Biol Chem, 273, 21608-21615.  
9463376 L.Esser, C.R.Wang, M.Hosaka, C.S.Smagula, T.C.Südhof, and J.Deisenhofer (1998).
Synapsin I is structurally similar to ATP-utilizing enzymes.
  EMBO J, 17, 977-984.
PDB codes: 1auv 1aux
  9774640 M.Gebauer, M.Zeiner, and U.Gehring (1998).
Interference between proteins Hap46 and Hop/p60, which bind to different domains of the molecular chaperone hsp70/hsc70.
  Mol Cell Biol, 18, 6238-6244.  
  9563818 R.Jaenicke (1998).
Protein self-organization in vitro and in vivo: partitioning between physical biochemistry and cell biology.
  Biol Chem, 379, 237-243.  
9187647 A.Joachimiak (1997).
Capturing the misfolds: chaperone-peptide-binding motifs.
  Nat Struct Biol, 4, 430-434.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.