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Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78.

Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H - PLoS ONE (2010)

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Affiliation: Structural Genomics Consortium, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Unlabelled: The 70-kDa heat shock proteins (Hsp70) are chaperones with central roles in processes that involve polypeptide remodeling events. Hsp70 proteins consist of two major functional domains: an N-terminal nucleotide binding domain (NBD) with ATPase activity, and a C-terminal substrate binding domain (SBD). We present the first crystal structures of four human Hsp70 isoforms, those of the NBDs of HSPA1L, HSPA2, HSPA5 and HSPA6. As previously with Hsp70 family members, all four proteins crystallized in a closed cleft conformation, although a slight cleft opening through rotation of subdomain IIB was observed for the HSPA5-ADP complex. The structures presented here support the view that the NBDs of human Hsp70 function by conserved mechanisms and contribute little to isoform specificity, which instead is brought about by the SBDs and by accessory proteins.

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Crystal structures of the human Hsp70 ATPase domains.(A) The structure of the HSPA5/BiP NBD in complex with CaADP at 2.4 Å resolution. (B) Superposition of the five Hsp70 NBD structures determined in this study. Dark blue, HSPA1A; yellow, HSPA1L; cyan, HSPA2; red, HSPA6; green, HSPA5/BiP. (C) Cartoon representation of HSPA6, colored to illustrate rms differences in Cα-positions between HSPA6 and HSPA1L (left), HSPA6 and HSPA5 (center), and HSPA6 and DnaK (right).
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pone-0008625-g004: Crystal structures of the human Hsp70 ATPase domains.(A) The structure of the HSPA5/BiP NBD in complex with CaADP at 2.4 Å resolution. (B) Superposition of the five Hsp70 NBD structures determined in this study. Dark blue, HSPA1A; yellow, HSPA1L; cyan, HSPA2; red, HSPA6; green, HSPA5/BiP. (C) Cartoon representation of HSPA6, colored to illustrate rms differences in Cα-positions between HSPA6 and HSPA1L (left), HSPA6 and HSPA5 (center), and HSPA6 and DnaK (right).

Mentions: The overall structures of the four human Hsp70 ATPase domains that were determined here for the first time all closely resemble the structure of HSPA1A and related previously determined structures (Figure 4). The HSPA1A NBD structure determined by us was virtually identical with the HSPA1A NBD structure published previously (PDB entry 1HJO; [39]). The canonical Hsp70 fold, with the common placement of secondary structural elements, was also observed for HSPA5/BiP, the least conserved member of the five proteins studied by us (Figure 4A). Pairwise comparison among these NBDs shows that for ∼70% of the backbone traces the rms difference is below 0.5 Å (Figure 4B). The largest rms deviation in the Cα positions was found for HSPA5, where the overall rms value is higher than 1.3 Å (only 17% of the backbone trace shows an rms difference lower than 0.5 Å). To illustrate this we color coded the rmsd in Cα atom positions between the pairs HSPA6 - HSPA1L, HSPA6 - HSPA5, and HSPA6 - E.coli DnaK, and mapped them onto the structure of HSPA6 (Figure 4C). This analysis shows that the most prominent difference between the HSPA5 and the canonical Hsp70 structures is a shift in subdomain IIB.


Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78.

Wisniewska M, Karlberg T, Lehtiö L, Johansson I, Kotenyova T, Moche M, Schüler H - PLoS ONE (2010)

Crystal structures of the human Hsp70 ATPase domains.(A) The structure of the HSPA5/BiP NBD in complex with CaADP at 2.4 Å resolution. (B) Superposition of the five Hsp70 NBD structures determined in this study. Dark blue, HSPA1A; yellow, HSPA1L; cyan, HSPA2; red, HSPA6; green, HSPA5/BiP. (C) Cartoon representation of HSPA6, colored to illustrate rms differences in Cα-positions between HSPA6 and HSPA1L (left), HSPA6 and HSPA5 (center), and HSPA6 and DnaK (right).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2803158&req=5

pone-0008625-g004: Crystal structures of the human Hsp70 ATPase domains.(A) The structure of the HSPA5/BiP NBD in complex with CaADP at 2.4 Å resolution. (B) Superposition of the five Hsp70 NBD structures determined in this study. Dark blue, HSPA1A; yellow, HSPA1L; cyan, HSPA2; red, HSPA6; green, HSPA5/BiP. (C) Cartoon representation of HSPA6, colored to illustrate rms differences in Cα-positions between HSPA6 and HSPA1L (left), HSPA6 and HSPA5 (center), and HSPA6 and DnaK (right).
Mentions: The overall structures of the four human Hsp70 ATPase domains that were determined here for the first time all closely resemble the structure of HSPA1A and related previously determined structures (Figure 4). The HSPA1A NBD structure determined by us was virtually identical with the HSPA1A NBD structure published previously (PDB entry 1HJO; [39]). The canonical Hsp70 fold, with the common placement of secondary structural elements, was also observed for HSPA5/BiP, the least conserved member of the five proteins studied by us (Figure 4A). Pairwise comparison among these NBDs shows that for ∼70% of the backbone traces the rms difference is below 0.5 Å (Figure 4B). The largest rms deviation in the Cα positions was found for HSPA5, where the overall rms value is higher than 1.3 Å (only 17% of the backbone trace shows an rms difference lower than 0.5 Å). To illustrate this we color coded the rmsd in Cα atom positions between the pairs HSPA6 - HSPA1L, HSPA6 - HSPA5, and HSPA6 - E.coli DnaK, and mapped them onto the structure of HSPA6 (Figure 4C). This analysis shows that the most prominent difference between the HSPA5 and the canonical Hsp70 structures is a shift in subdomain IIB.

Bottom Line: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions.Please note that a web plugin is required to access this enhanced functionality.Instructions for the installation and use of the web plugin are available in Text S1.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

Unlabelled: The 70-kDa heat shock proteins (Hsp70) are chaperones with central roles in processes that involve polypeptide remodeling events. Hsp70 proteins consist of two major functional domains: an N-terminal nucleotide binding domain (NBD) with ATPase activity, and a C-terminal substrate binding domain (SBD). We present the first crystal structures of four human Hsp70 isoforms, those of the NBDs of HSPA1L, HSPA2, HSPA5 and HSPA6. As previously with Hsp70 family members, all four proteins crystallized in a closed cleft conformation, although a slight cleft opening through rotation of subdomain IIB was observed for the HSPA5-ADP complex. The structures presented here support the view that the NBDs of human Hsp70 function by conserved mechanisms and contribute little to isoform specificity, which instead is brought about by the SBDs and by accessory proteins.

Enhanced version: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Show MeSH
Related in: MedlinePlus