The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function
The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP a...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-09-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/9/10/543 |
| _version_ | 1818279922886508544 |
|---|---|
| author | Graham Chakafana Tawanda Zininga Addmore Shonhai |
| author_facet | Graham Chakafana Tawanda Zininga Addmore Shonhai |
| author_sort | Graham Chakafana |
| collection | DOAJ |
| description | The heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones. |
| first_indexed | 2024-12-12T23:41:02Z |
| format | Article |
| id | doaj.art-956cc024d18e474ba38ed8ad7362824f |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-12T23:41:02Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-956cc024d18e474ba38ed8ad7362824f2022-12-22T00:07:11ZengMDPI AGBiomolecules2218-273X2019-09-0191054310.3390/biom9100543biom9100543The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s FunctionGraham Chakafana0Tawanda Zininga1Addmore Shonhai2Department of Biochemistry, University of Venda, Private Bags X5050, Thohoyandou 0950, South AfricaDepartment of Biochemistry, University of Venda, Private Bags X5050, Thohoyandou 0950, South AfricaDepartment of Biochemistry, University of Venda, Private Bags X5050, Thohoyandou 0950, South AfricaThe heat shock 70 (Hsp70) family of molecular chaperones plays a central role in maintaining cellular proteostasis. Structurally, Hsp70s are composed of an N-terminal nucleotide binding domain (NBD) which exhibits ATPase activity, and a C-terminal substrate binding domain (SBD). The binding of ATP at the NBD and its subsequent hydrolysis influences the substrate binding affinity of the SBD through allostery. Similarly, peptide binding at the C-terminal SBD stimulates ATP hydrolysis by the N-terminal NBD. Interdomain communication between the NBD and SBD is facilitated by a conserved linker segment. Hsp70s form two main subgroups. Canonical Hsp70 members generally suppress protein aggregation and are also capable of refolding misfolded proteins. Hsp110 members are characterized by an extended lid segment and their function tends to be largely restricted to suppression of protein aggregation. In addition, the latter serve as nucleotide exchange factors (NEFs) of canonical Hsp70s. The linker of the Hsp110 family is less conserved compared to that of the canonical Hsp70 group. In addition, the linker plays a crucial role in defining the functional features of these two groups of Hsp70. Generally, the linker of Hsp70 is quite small and varies in size from seven to thirteen residues. Due to its small size, any sequence variation that Hsp70 exhibits in this motif has a major and unique influence on the function of the protein. Based on sequence data, we observed that canonical Hsp70s possess a linker that is distinct from similar segments present in Hsp110 proteins. In addition, Hsp110 linker motifs from various genera are distinct suggesting that their unique features regulate the flexibility with which the NBD and SBD of these proteins communicate via allostery. The Hsp70 linker modulates various structure-function features of Hsp70 such as its global conformation, affinity for peptide substrate and interaction with co-chaperones. The current review discusses how the unique features of the Hsp70 linker accounts for the functional specialization of this group of molecular chaperones.https://www.mdpi.com/2218-273X/9/10/543heat shock protein 70linkerallosterychaperone |
| spellingShingle | Graham Chakafana Tawanda Zininga Addmore Shonhai The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function Biomolecules heat shock protein 70 linker allostery chaperone |
| title | The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function |
| title_full | The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function |
| title_fullStr | The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function |
| title_full_unstemmed | The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function |
| title_short | The Link That Binds: The Linker of Hsp70 as a Helm of the Protein’s Function |
| title_sort | link that binds the linker of hsp70 as a helm of the protein s function |
| topic | heat shock protein 70 linker allostery chaperone |
| url | https://www.mdpi.com/2218-273X/9/10/543 |
| work_keys_str_mv | AT grahamchakafana thelinkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction AT tawandazininga thelinkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction AT addmoreshonhai thelinkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction AT grahamchakafana linkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction AT tawandazininga linkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction AT addmoreshonhai linkthatbindsthelinkerofhsp70asahelmoftheproteinsfunction |