Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Abstract

Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

“…Both our findings and the earlier understanding of the dynamics of protein fragments vis-à-vis the Arg/N-end rule pathway (7,9,12,14,23) indicate that the topologically unique nature of N-degrons (their main determinant is a single N-terminal residue) has significantly contributed to coevolution of nonprocessive proteases and their cleavage sites in cellular proteins. As described above, these cleavage sites tend to be conserved in evolution, and their P1′ residues often yield C-terminal fragments whose N-terminal residues are recognized by the Arg/N-end rule pathway (Figs.…”

“…For example, cell movements involve calpain-mediated, spatiotemporally controlled cleavages of cytoskeletal proteins (5). Proteolysis by calpains plays many other roles as well, including their major functions in the brain and muscle (6)(7)(8). Despite the obvious biological importance of calpains, the functional understanding of calpain-generated specific protein fragments and their effects on oligomeric protein complexes (in which these fragments are formed and initially reside) is just beginning.…”

Sleep and Development in Genetically Tractable Model Organisms

“…Stress response pathways, e.g., insulin/insulin-like (IIS) or heat-shock factor (HSF)-dependent signaling, are activated by disrupting sleep in flies and worms (Shaw et al 2000(Shaw et al , 2002Cirelli et al 2006;Naidoo 2009;Brown and Naidoo 2010;Varshavsky 2012;Driver et al 2013;Nagy et al 2014). These findings indicate that, like mammalian sleep, invertebrate sleep can be a period of heightened vulnerability when otherwise benign stimuli act as stressors (Shaw et al 2002;Driver et al 2013;Nagy et al 2014).…”

Liat1, an arginyltransferase-binding protein whose evolution among primates involved changes in the numbers of its 10-residue repeats

“…Many, possibly most, of these proteins are conditionally or constitutively short-lived substrates of the Arg/N-end rule pathway (Fig. 1A) (14,15,20,26, and references therein). In contrast, there were, until now, no analyzed protein ligands of R-transferase that did not appear to be its substrates.…”