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Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
HSPs are critical in cell proteostasis through their ability to fold nascent proteins and refold damaged proteins. Importantly, HSP70, HSP40, and HSP90 are all critical in ensuring proteostasis by facilitating proper folding of newly translated proteins exiting ribosomes at the endoplasmic reticulum (ER) (24, 29, 92). Ribosome-associated co-chaperones (MPP1 and HSPA14) transfer nascent proteins to non-ribosomal HSP70 chaperone complexes (HSP70 and HSP40), which facilitate the native folding of proteins requiring a high degree of complex co-translational folding (some subsets may be transferred to HSP90 for further processing via Hsp70-Hsp90 Organizing Protein (HOP)) (88, 92). In addition to the folding of nascent proteins, these HSPs are involved in the refolding of damaged or unfolded proteins. After recognition, recruitment, and transfer of unfolded proteins via co-chaperone HSP40, protein-bound HSP70 undergoes adenosine triphosphate (ATP) cycling via nucleotide exchange factors to cause conformational changes in HSP70—ultimately enabling native folding based on amino acid characteristics (i.e., polarity) (29). If proteins are unable to refold via HSP70, they can be passed along to chaperonins (i.e., HSP60 and HSP10) and/or HSP90 for extended processing. If it is not possible for the protein to fold into its native form via its interactions with these chaperones, it is likely to be tagged for degradation via the ubiquitin–proteasome system (UPS).
Maple syrup urine disease (branched-chain oxoaciduria)
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The fundamental defect is in the activity of the branched-chain oxoacid dehydrogenase multienzyme complex (Figures 19.1 and 19.2) [1, 6, 7]. The components are E1 (a decarboxylase), E2 (an acyl transferase), and E3 (a flavoprotein lipoamide dehydrogenase (dihydrolipoyl dehydrogenase)). E1 is composed of two proteins in an α2β2 structure. The enzyme complex, which was purified to homogeneity by Pettit and colleagues [7], is analogous to the pyruvate and the 2-ketoglutarate dehydrogenase complexes; in fact, the E3 component of the three complexes is the same protein, and in E3 deficiency (Chapter 50) defective activity of each dehydrogenase enzyme results. Expression studies have shown that the complex does not assemble spontaneously; the E1 α and β proteins require chaperonins for folding and assembly [8].
Recombinant Antibodies
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Melvyn Little, Sergey M. Kipriyanov
Phage presentation of antibodies usually involves either single-chain antibodies (scFvs, see below) consisting of only the variable domains of antibody heavy and light chains joined by a flexible peptide linker or Fabs. In both cases, the heavy or light chain is fused to pIII or pVIII and the two chains dimerize to form an antigen-binding antibody fragment in the periplasmic space. The C-terminal domain of phage pIII or pVIII remains attached to the cytoplasmic membrane until it is incorporated into the secreted phage particle. To increase the copy number of each antibody, GroE chaperonins have been coexpressed during phage packaging (Söderlind et al., 1993). This led to an almost two hundred-fold increase in the phage titer from ~4 × 1011 cfu/ml to 7 × 1013cfu/ml.
Effects of 4-phenylbutyric acid on the development of diabetic retinopathy in diabetic rats: regulation of endoplasmic reticulum stress-oxidative activation
Published in Archives of Physiology and Biochemistry, 2023
Amany Abdel-Ghaffar, Ghada G. Elhossary, Atef M. Mahmoud, Amany H. M. Elshazly, Olfat A. Hassanin, Anisa Saleh, Sahar M. Mansour, Fatma G. Metwally, Laila K. Hanafy, Sawsan H. Karam, Neveen Darweesh, Ahmed Mostafa Ata
Molecules showing chaperone-like activities that mimic or modulate endogenous chaperone activity can therefore be used as therapeutic agents for diseases in which ER dysfunction is a contributing factor in the disease process. These molecules can be classified into three groups which are pharmacological, molecular, and chemical chaperones. Molecular chaperones tend to bind to hydrophobic residues in the unfolded protein after recognising them. They aid protein stabilisation, translocation across membranes and assembly, introduce the misfolded proteins to the proteolytic machinery for disposal and prevent unstable proteins from aggregating. Nucleoplasmins, chaperonins, and heat shock proteins (Hsp) are considered molecular chaperones (Oikawa et al.2007).
Proteome microarray technology and application: higher, wider, and deeper
Published in Expert Review of Proteomics, 2019
Huan Qi, Fei Wang, Sheng-ce Tao
Differences between the proteins immobilized on microarrays and their counterparts in physiological conditions clearly exist. Traditionally, the proteins used for proteome microarray construction are prepared by an expression system, either cell-based or cell-free. The differences between in post-translational modifications found in expression systems and in physiological conditions might result in different binding patterns. In addition, differences in modification patterns, lack of knowledge of modification sites and functional groups may add extra difficulties to proteins preparation for proteome microarray construction. Protein folding might also be variable among different expression systems because of differences in chaperonins.
Hydrogen deuterium exchange mass spectrometry applied to chaperones and chaperone-assisted protein folding
Published in Expert Review of Proteomics, 2019
Florian Georgescauld, Thomas E. Wales, John R. Engen
Chaperonins constitute an essential class of chaperones formed by two identical rings of about 0.5 MDa each, stacked back to back. Two groups of chaperonins exist: group I chaperonins present in bacteria (GroEL/GroES), mitochondria (Hsp60/Hsp10) and chloroplasts (Cpn60/Cpn10), and group II chaperonins present in eukaryotes (TriC also called CCT) and archaea (thermosome). GroEL/GroES, the most studied chaperonin, is the only essential molecular chaperone in E. coli and interacts with 250 different cytosolic proteins [16]. About 80 of the 250 proteins are ‘strictly dependent’ substrates (or class III substrates) because at 37°C they are unable to acquire their native structure without help from GroEL/GroES and aggregate rapidly. Natural substrates of GroEL/GroES are frequently proteins that include a TIM-barrel domain, with half of the chaperone substrates being of this variety. GroEL consists of a double ring of seven identical subunits forming a central cavity that can hold proteins between 20 and 60 kDa in size. In the presence of ATP and GroES, one substrate protein at a time will be encapsulated for about 10 s in the ‘nano-compartment’ formed by GroEL/GroES, so that folding can occur. Determining how GroEL/GroES actively promotes folding of the encapsulated substrate protein is a key question in the protein folding field. The eukaryotic cognate of GroEL is the chaperonin TRiC, composed of two rings of eight different paralogous subunits (reviewed in [17]). No analogous GroES lid covers the rings in TRiC, but a built-in lid is formed from apical protrusions of each subunit. Substrates of prokaryotic and eukaryotic chaperonins are different, suggesting different functional mechanisms.