Exploring Fold Space Preferences of New-born and Ancient Protein Superfamilies

The evolution of proteins is one of the fundamental processes that has delivered the diversity and complexity of life we see around ourselves today. While we tend to define protein evolution in terms of sequence level mutations, insertions and deletions, it is hard to translate these processes to a more complete picture incorporating a polypeptide's structure and function. By considering how protein structures change over time we can gain an entirely new appreciation of their long-term evolutionary dynamics. In this work we seek to identify how populations of proteins at different stages of evolution explore their possible structure space. We use an annotation of superfamily age to this space and explore the relationship between these ages and a diverse set of properties pertaining to a superfamily's sequence, structure and function. We note several marked differences between the populations of newly evolved and ancient structures, such as in their length distributions, secondary structure content and tertiary packing arrangements. In particular, many of these differences suggest a less elaborate structure for newly evolved superfamilies when compared with their ancient counterparts. We show that the structural preferences we report are not a residual effect of a more fundamental relationship with function. Furthermore, we demonstrate the robustness of our results, using significant variation in the algorithm used to estimate the ages. We present these age estimates as a useful tool to analyse protein populations. In particularly, we apply this in a comparison of domains containing greek key or jelly roll motifs

Infralimbic and dorsal raphé microinjection of the 5-HT1B receptor agonist CP-93,129: attenuation of aggressive behavior in CFW male mice

RATIONALE: Aggressive behavior and impaired impulse control have been associated with dysregulations in the serotonergic system and with impaired functioning of the prefrontal cortex. 5-HT(1B) receptors have been shown to specifically modulate several types of offensive aggression. OBJECTIVE: To characterize the relative importance of 2 populations of 5-HT(1B) receptors in the dorsal raphé nucleus (DRN) and infralimbic cortex (ILC) in the modulation of aggressive behavior. METHODS: Male CFW mice were conditioned on a fixed-ratio 5 schedule of reinforcement to self-administer a 6% (w/v) alcohol solution. Mice repeatedly engaged in 5 min aggressive confrontations until aggressive behavior stabilized. Next, a cannula was implanted into either the DRN or the ILC. After recovery, mice were tested for aggression after self-administration of either 1.0 g/kg alcohol or water prior to a microinjection of the 5-HT(1B) agonist, CP-93,129 (0–1.0 µg/infusion). RESULTS: In both the DRN and ILC, CP-93,129 reduced aggressive behaviors after both water and alcohol self-administration. Intra-raphé CP-93,129 dose-dependently reduced both aggressive and locomotor behaviors. However, the anti-aggressive effects of intra-cortical CP-93,129 were behaviorally specific. CONCLUSIONS: These findings highlight the importance of the serotonergic system in the modulation of aggression and suggest that the behaviorally specific effects of 5-HT(1B) receptor agonists are regionally selective. 5-HT(1B) receptors in a medial subregion of the prefrontal cortex, the ILC, appear to be critically involved in the attenuation of species-typical levels of aggression

Opponency Revisited: Competition and Cooperation Between Dopamine and Serotonin

Affective valence lies on a spectrum ranging from punishment to reward. The coding of such spectra in the brain almost always involves opponency between pairs of systems or structures. There is ample evidence for the role of dopamine in the appetitive half of this spectrum, but little agreement about the existence, nature, or role of putative aversive opponents such as serotonin. In this review, we consider the structure of opponency in terms of previous biases about the nature of the decision problems that animals face, the conflicts that may thus arise between Pavlovian and instrumental responses, and an additional spectrum joining invigoration to inhibition. We use this analysis to shed light on aspects of the role of serotonin and its interactions with dopamine