Hsp70 chaperone dynamics and molecular mechanism
1Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH-Alliance, Heidelberg, Germany.
Trends in Biochemical Sciences
|September 10, 2013
Summary
Heat shock protein (Hsp)70 uses an allosteric mechanism involving its nucleotide-binding domain (NBD) and substrate-binding domain (SBD) to regulate protein folding. Recent structural and biophysical studies reveal dynamic conformations critical for Hsp70 chaperone function.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Heat shock protein (Hsp)70 functions as a molecular chaperone, crucial for protein homeostasis.
- Hsp70 activity is regulated by an allosteric mechanism linking nucleotide binding/hydrolysis to substrate binding.
- Two distinct conformational states of Hsp70, regulated by ATP, govern substrate affinity and release.
Purpose of the Study:
- To review recent structural and biophysical insights into Hsp70.
- To elucidate the dynamic mechanism of Hsp70 in assisting protein folding.
- To discuss the conformational states of Hsp70.
Main Methods:
- Structural biology techniques (e.g., X-ray crystallography, cryo-EM) to determine Hsp70 conformations.
- Biophysical methods (e.g., spectroscopy, kinetics) to probe Hsp70 dynamics.
- Allosteric mechanism analysis.
Main Results:
- Structural data for the high-affinity polypeptide-bound state has been available.
- The low-affinity, open-cleft conformation of Hsp70 was recently elucidated.
- Biophysical studies highlight the dynamic nature of Hsp70 and its mechanism.
Conclusions:
- Hsp70s exist in at least two distinct conformational states.
- Understanding these conformations and dynamics is key to Hsp70's chaperone mechanism.
- Recent advances provide a clearer picture of how Hsp70s facilitate protein folding.
Related Concept Videos
03:00Molecular Chaperones and Protein Folding
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
03:00Molecular Chaperones and Protein Folding
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
01:26Bacterial Protein Maturation
Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
01:37Energy to Drive Translocation
Mitochondrial protein import is powered by two distinct energy sources: ATP hydrolysis and electrochemical potential across the inner membrane. Newly synthesized precursors are bound by cytosolic chaperones of the Hsp70 family, which guide them to the import receptors on the mitochondrial surface. Utilizing the energy of ATP hydrolysis, Hsp70 chaperones transfer these precursors to the TOM receptors on the mitochondrial outer membrane.
Generally, polypeptides are unfolded by two distinct...
Generally, polypeptides are unfolded by two distinct...
02:41Protein Complex Assembly
Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types. Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Many viruses self-assemble into a fully functional unit using the infected host cell to...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...