Disulfide bonds are generally not used to stabilize proteins in the cytosolic compartments of bacteria or eukaryotic cells, owing to the chemically reducing nature of those environments. In contrast, certain thermophilic archaea use disulfide bonding as a major mechanism for protein stabilization. Here, we provide a current survey of completely sequenced genomes, applying computational methods to estimate the use of disulfide bonding across the Archaea. Microbes belonging to the Crenarchaeal branch, which are essentially all hyperthermophilic, are universally rich in disulfide bonding while lesser degrees of disulfide bonding are found among the thermophilic Euryarchaea, excluding those that are methanogenic. The results help clarify which parts of the archaeal lineage are likely to yield more examples and additional specific data on protein disulfide bonding, as increasing genomic sequencing efforts are brought to bear. 1. Introduction The archaea inhabit incredibly diverse environments [1]. Many species thrive at temperatures exceeding 100°C. Growth at such high temperatures presents special challenges, among the most serious being the problem of stabilizing cellular proteins in their natively folded configurations. For many proteins, the folded configuration is only modestly favored energetically compared to the unfolded state [2], and high temperatures irreversibly unfold the vast majority of proteins derived from organisms that live at moderate temperatures. The question of how thermophilic proteins are stabilized has therefore attracted considerable attention over the years [3, 4]. Numerous studies have concluded that thermophilic proteins are stabilized by a wide array of forces and effects, which appear to present themselves to different degrees in different proteins and organisms [3, 5–8]. Increased atomic packing [9, 10], hydrophobic interactions [11], ionic interactions [9, 12–14], and shorter loops [15] have all been noted as providing additional noncovalent stabilization in thermophilic proteins. More unexpected was the realization that disulfide bonding—a much stronger, covalent force—might play an important role in some organisms [16, 17]. A striking clue came when the structure of the enzyme adenylosuccinate lyase from the hyperthermophilic Pyrobaculum aerophilum revealed that the six cysteines in the protein chain pair up to form three disulfide bonds [17]. This prompted the development by Mallick et al. [16] of genomic calculations, which supported the idea that some thermophiles use disulfide bonding as a major mechanism for protein
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