PubMed · 13070425
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I ABELIN. 1953-02-15. [Thyroxin resistance].. https://doi.org/10.1007/bf01473371
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The discovery of the 20S proteasome (multicatalytic proteinase complex) was followed by the recognition that this multisubunit macromolecule is the proteolytic core of the 26S proteasome. Most of the research on extralysosomal proteolysis has concentrated on the role of the 26S proteasome in the ubiquitin-dependent proteolytic pathway. However, little attention has been directed toward the possible involvement of the proteasome in ubiquitin-independent proteolysis. In the past few years, many publications have provided evidence that both the 20S proteasome and the 26S proteasome can degrade some proteins in an ubiquitin-independent manner. Furthermore, it is becoming clear that demonstration of ubiquitin-protein conjugates after exposure of cells to proteasome inhibitors does not eliminate the possibility that the same protein can also be degraded by the proteasome without ubiquitination. The possible mechanisms of degradation of an unmodified protein by the 20S proteasome are discussed. These include targeting, protein unfolding, and opening of the gated channel to the catalytic sites. It is reasonable to assume that in the future the number of proteins recognized as substates of the ubiquitin-independent pathway will continue to increase, and that the metabolic significance of this pathway will be clarified.
Oxidative phosphorylation involves the coupling of ATP synthesis to the proton-motive force that is generated typically by a series of membrane-bound electron transfer complexes, which ultimately reduce an exogenous terminal electron acceptor. This is not the case with Pyrococcus furiosus, an archaeon that grows optimally near 100 degrees C. It has an anaerobic respiratory system that consists of a single enzyme, a membrane-bound hydrogenase. Moreover, it does not require an added electron acceptor as the enzyme reduces protons, the simplest of acceptors, to hydrogen gas by using electrons from the cytoplasmic redox protein ferredoxin. It is demonstrated that the production of hydrogen gas by membrane vesicles of P. furiosus is directly coupled to the synthesis of ATP by means of a proton-motive force that has both electrochemical and pH components. Such a respiratory system enables rationalization in this organism of an unusual glycolytic pathway that was previously thought not to conserve energy. It is now clear that the use of ferredoxin in place of the expected NAD as the electron acceptor for glyceraldehyde 3-phosphate oxidation enables energy to be conserved by hydrogen production. In addition, this simple respiratory mechanism readily explains why the growth yields of P. furiosus are much higher than could be accounted for if ATP synthesis occurred only by substrate-level phosphorylation. The ability of microorganisms such as P. furiosus to couple hydrogen production to energy conservation has important ramifications not only in the evolution of respiratory systems but also in the origin of life itself.
In the heme-based oxygen sensor Dos from Escherichia coli, one of the axial ligands (Met 95) of a six-coordinate heme can be replaced by external ligands such as O(2), NO, and CO, which causes a switch in phosphodiesterase activity. To gain insight into the bidirectional switching mechanism, we have studied the interaction of ligands with the sensor domain DosH by flash photolysis experiments with femtosecond time resolution. The internal ligand can be photodissociated from the ferrous heme and recombines with time constants of 7 and 35 ps. This is somewhat slower than recombination of the external ligands NO, with which picosecond rebinding occurs with unprecedented efficiency (>99%) with a predominant phase of approximately 5 ps, and O(2) (97% in 5 ps, Liebl, U., Bouzhir-Sima, L., Négrerie, M., Martin, J.-L., and Vos, M. H. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 12771-12776). Dissociated CO displays geminate rebinding in 1.5 ns with a very high yield (60%). Together these results indicate that the heme environment provides a very tight pocket for external ligands, presumably preventing frequent switching events. Additional CO dissociation and rebinding experiments on a longer time scale reveal that (a) Met 95 binding, in 100 micros, occurs in competition with bimolecular CO binding, and (b) subsequent replacement of Met 95 by CO on the millisecond time scale occurs faster than in rapid-mixing experiments, suggesting a slow further relaxation. A minimal ligand binding model is proposed that suggests that Met 95 displacement from the heme is facilitated by the presence of an external ligand in the heme environment. Furthermore, the orders of magnitude difference between Met 95 binding after dissociation of internal and external ligands, as well as the spectral characteristics of photodissociation intermediates, indicate substantial rearrangement of the heme environment associated with ligand sensing. Further remarkable observations include evidence for stable (>4 ns) photooxidation of six-coordinate ferrous heme, with a quantum yield of 4-8%.