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The crystal structure of the putative peptide-binding fragment from the human Hsp40 protein Hdj1.

Hu J, Wu Y, Li J, Qian X, Fu Z, Sha B - BMC Struct. Biol. (2008)

Bottom Line: When compared with another Hsp40 Sis1 structure, the domain I of Hdj1 is rotated by 7.1 degree from the main body of the molecule, which makes the cleft between the two Hdj1 monomers smaller that that of Sis1.This structural observation indicates that the domain I of Hsp40 may possess significant flexibility.We propose an "anchoring and docking" model for Hsp40 to utilize the flexibility of domain I to interact with non-native polypeptides and transfer them to Hsp70.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. hujunbin@uab.edu

ABSTRACT

Background: The mechanism by which Hsp40 and other molecular chaperones recognize and interact with non-native polypeptides is a fundamental question. How Hsp40 co-operates with Hsp70 to facilitate protein folding is not well understood. To investigate the mechanisms, we determined the crystal structure of the putative peptide-binding fragment of Hdj1, a human member of the type II Hsp40 family.

Results: The 2.7A structure reveals that Hdj1 forms a homodimer in the crystal by a crystallographic two-fold axis. The Hdj1 dimer has a U-shaped architecture and a large cleft is formed between the two elongated monomers. When compared with another Hsp40 Sis1 structure, the domain I of Hdj1 is rotated by 7.1 degree from the main body of the molecule, which makes the cleft between the two Hdj1 monomers smaller that that of Sis1.

Conclusion: This structural observation indicates that the domain I of Hsp40 may possess significant flexibility. This flexibility may be important for Hsp40 to regulate the size of the cleft. We propose an "anchoring and docking" model for Hsp40 to utilize the flexibility of domain I to interact with non-native polypeptides and transfer them to Hsp70.

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The surface potential drawings around the Hdj1 and Sis1 peptide-binding sites determined by Swiss-PDBviewer. Blue and red denote positively and negatively charged regions, respectively. a) Surface potential drawing presentation of the Hdj1 peptide-binding site. The residues of Hdj1 involved in forming the peptide-binding site are labeled in black. The Lysine residues involved in binding the Hsp70 C-terminal EEVD motifs are labeled in white. b) Surface potential drawing presentation of the Sis1 peptide-binding site.
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Figure 4: The surface potential drawings around the Hdj1 and Sis1 peptide-binding sites determined by Swiss-PDBviewer. Blue and red denote positively and negatively charged regions, respectively. a) Surface potential drawing presentation of the Hdj1 peptide-binding site. The residues of Hdj1 involved in forming the peptide-binding site are labeled in black. The Lysine residues involved in binding the Hsp70 C-terminal EEVD motifs are labeled in white. b) Surface potential drawing presentation of the Sis1 peptide-binding site.

Mentions: Molecular chaperone Hsp40 can interact and stabilize the non-native polypeptides and prevent them from forming aggregations. The peptide-binding sites of both type I and type II Hsp40s for the non-native polypeptides have been located on the molecular surface of domain I. The Hsp40s may bind the non-native polypeptides through hydrophobic interactions [14-16]. When we examined the peptide-binding site on the domain I of Hdj1 structure, several hydrophobic residues were identified to participate in forming the peptide-binding site. These residues include L168, M183, I185 and F237 (Fig. 4). The hydrophobicity of these residues is well conserved among all species. However, a polar residue, H166, was also identified to be involved in constituting the peptide-binding pocket (Fig. 4). This Histidine residue is conserved for type II Hsp40s among all species except for yeast as shown in sequence alignment (Fig. 3). We reason that H166 may play an important role in positioning the side chains from Pro, Phe or Tyr residues through van der waals interactions.


The crystal structure of the putative peptide-binding fragment from the human Hsp40 protein Hdj1.

Hu J, Wu Y, Li J, Qian X, Fu Z, Sha B - BMC Struct. Biol. (2008)

The surface potential drawings around the Hdj1 and Sis1 peptide-binding sites determined by Swiss-PDBviewer. Blue and red denote positively and negatively charged regions, respectively. a) Surface potential drawing presentation of the Hdj1 peptide-binding site. The residues of Hdj1 involved in forming the peptide-binding site are labeled in black. The Lysine residues involved in binding the Hsp70 C-terminal EEVD motifs are labeled in white. b) Surface potential drawing presentation of the Sis1 peptide-binding site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254625&req=5

Figure 4: The surface potential drawings around the Hdj1 and Sis1 peptide-binding sites determined by Swiss-PDBviewer. Blue and red denote positively and negatively charged regions, respectively. a) Surface potential drawing presentation of the Hdj1 peptide-binding site. The residues of Hdj1 involved in forming the peptide-binding site are labeled in black. The Lysine residues involved in binding the Hsp70 C-terminal EEVD motifs are labeled in white. b) Surface potential drawing presentation of the Sis1 peptide-binding site.
Mentions: Molecular chaperone Hsp40 can interact and stabilize the non-native polypeptides and prevent them from forming aggregations. The peptide-binding sites of both type I and type II Hsp40s for the non-native polypeptides have been located on the molecular surface of domain I. The Hsp40s may bind the non-native polypeptides through hydrophobic interactions [14-16]. When we examined the peptide-binding site on the domain I of Hdj1 structure, several hydrophobic residues were identified to participate in forming the peptide-binding site. These residues include L168, M183, I185 and F237 (Fig. 4). The hydrophobicity of these residues is well conserved among all species. However, a polar residue, H166, was also identified to be involved in constituting the peptide-binding pocket (Fig. 4). This Histidine residue is conserved for type II Hsp40s among all species except for yeast as shown in sequence alignment (Fig. 3). We reason that H166 may play an important role in positioning the side chains from Pro, Phe or Tyr residues through van der waals interactions.

Bottom Line: When compared with another Hsp40 Sis1 structure, the domain I of Hdj1 is rotated by 7.1 degree from the main body of the molecule, which makes the cleft between the two Hdj1 monomers smaller that that of Sis1.This structural observation indicates that the domain I of Hsp40 may possess significant flexibility.We propose an "anchoring and docking" model for Hsp40 to utilize the flexibility of domain I to interact with non-native polypeptides and transfer them to Hsp70.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. hujunbin@uab.edu

ABSTRACT

Background: The mechanism by which Hsp40 and other molecular chaperones recognize and interact with non-native polypeptides is a fundamental question. How Hsp40 co-operates with Hsp70 to facilitate protein folding is not well understood. To investigate the mechanisms, we determined the crystal structure of the putative peptide-binding fragment of Hdj1, a human member of the type II Hsp40 family.

Results: The 2.7A structure reveals that Hdj1 forms a homodimer in the crystal by a crystallographic two-fold axis. The Hdj1 dimer has a U-shaped architecture and a large cleft is formed between the two elongated monomers. When compared with another Hsp40 Sis1 structure, the domain I of Hdj1 is rotated by 7.1 degree from the main body of the molecule, which makes the cleft between the two Hdj1 monomers smaller that that of Sis1.

Conclusion: This structural observation indicates that the domain I of Hsp40 may possess significant flexibility. This flexibility may be important for Hsp40 to regulate the size of the cleft. We propose an "anchoring and docking" model for Hsp40 to utilize the flexibility of domain I to interact with non-native polypeptides and transfer them to Hsp70.

Show MeSH
Related in: MedlinePlus