ATP-independent molecular chaperone activity generated under reducing conditions
Axel Leppert1,2, Gefei Chen1, Danai Lianoudaki2
1Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Protein Science : a Publication of the Protein Society
|July 28, 2022
Summary
Extracellular molecular chaperones like Bri2 BRICHOS gain function under reducing conditions. They assemble into large structures, preventing extracellular protein aggregation and supporting proteostasis during reductive stress.
Area of Science:
- Biochemistry
- Molecular Biology
- Proteostasis
Background:
- Intracellular molecular chaperones are well-studied, but extracellular chaperones remain less understood.
- Extracellular proteins, stabilized by disulfide bonds, are vulnerable to aggregation in reducing environments.
Purpose of the Study:
- To elucidate the molecular chaperone functions of the extracellular Bri2 BRICHOS domain.
- To understand the activation mechanism and conditions favoring Bri2 BRICHOS chaperone activity.
Main Methods:
- Biochemical experiments
- Mass spectrometry
- Analysis of protein assembly and aggregation under reducing conditions.
Main Results:
- Bri2 BRICHOS exhibits chaperone activity specifically under reducing conditions.
- Monomeric Bri2 BRICHOS assembles into large oligomers via a disulfide bond relay mechanism.
- These assemblies inhibit reduction-induced aggregation of extracellular proteins.
Conclusions:
- A novel activation mechanism for an extracellular chaperone domain (Bri2 BRICHOS) has been identified.
- Reducing conditions trigger Bri2 BRICHOS assembly, enhancing its protective function against protein aggregation.
- This provides a mechanism to maintain extracellular proteostasis under reductive stress.
Related Concept Videos
03:00Molecular Chaperones and Protein Folding
18.3K
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...
18.3K
01:26Bacterial Protein Maturation
79
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...
79
01:37Energy to Drive Translocation
2.1K
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...
2.1K
01:19Translocation of Proteins into the Mitochondria
3.2K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.2K
01:28Protein Denaturation
4.8K
The function of proteins depends on their native three-dimensional structure, which is dictated by the amino acid sequence of the specific protein. Folding of the polypeptide chain takes place under specific conditions that energetically favor the folded conformation. In contrast, protein denaturation occurs spontaneously under unfavorable conditions that disrupt the integrity of the folded conformation. Thus, the chemical and physical environment of a protein, such as significant changes in pH...
4.8K
01:31Regulation of the Unfolded Protein Response
2.6K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.6K