Lecture 27 The mechanism of the rotary FoF1 ATPase (continued) Evolvability

Quantitation -180 mV pH = 8 0 mV pH = 7 PMF = = -240 mV thus ΔG H+ = FΔφ =96.5 x 0.24 = 21. kJ ΔG (ATP) = -31kJ/mol log([ADP][Pi]/[ATP]) ΔG ~ -50kJ/mole…how many protons needed? but transporters reduce ΔG for ATP… actually PMF ~ -220 mV

Evolvability = the capacity to generate heritable, selectable phenotype variation. This capacity has two components: (i) to reduce the potential lethality of mutations and (ii) to reduce the number of mutations needed to produce phenotypically novel traits. Bacteria and protista versus metazoa. Bacteria perfect their metabolic capacity/diversity. Metazoa capitalize on intercellular regulation. There is a large number of conserved sequences (cytoskeletal proteins, ribosomes, etc) and mechanisms (‘frozen accidents’). Conservation of very core processes (replication, division, synthesis) does not serve the only purpose of their perfection/optimization (constraint/embedment), but more to deconstraint their regulation, providing phenotypic variation for other (regulatory processes) on the basis of which the core processes are continuously coselected. If sequence is conserved, function is usually conserved too. Function can stay conserved when sequence is diverged. But only function is selectable!

Evolution of regulation of cellular processes is all based on inhibition. Core processes are conserved in all eukaryotes, their control is not. In metazoa, the entire evolution of development is under intercellular control regarding the time, place and conditions of function. In many cases evolution of regulatory inhibition is straightforward because many inhibitors are modified components of the process lacking effector domains and acting as dominant negative agents. (There are many examples of auto-inhibition by substrate-mimicking domains on the enzyme). Cyclins (chapter 21), Gluconeogenesis (see p in the book) Repression or activation of genes depends on exposure of NLS, dimerization, association with an inhibitory protein, competition for binding site, modifications of chromatin. In nerve terminals, a Ca-sensitive step is interposed in the normal pathway of unregulated secretion. Calmodulin is highly conserved, but due to its flexibility binds to a large variety of sequences. It is effective without having to be specific. Flexible systems of inhibition decrease requirements for mutational change

Weak linkages The absence of strict sequence and stipulation (rather modulation) facilitates a component’s or step accommodation to novelty Ca2+ regulation depends on many inputs (i) pumps, (ii) K+ channel activity, (iii) other ion channels regulated internally or externally Eukaryotic transcription is much more diverse compared to prokaryotic: cis and trans regulatory regions in genes, enhancers, repressors, multiple inputs Exploratory Mechanisms The best example is vertebrate adaptive immunity (sequnce variability) Dynamic exploration by cytoskeleton (stabilization and collapse of MT by different mechanisms) Mammalian limb and neural crest development are the examples

Compartmentalization, Redundancy, Robustness and Flexibility Compartmentalization reduces interdependence of processes Redundancy protects old functions as new arise Many paths lead to muscle differentiation even within the same organism. Genomic compartmentalization is controlled by master transcription factors There are usually many precursors for the same path of differentiation (muscle). Conserved patterns are easy to change (fly bristles) Cell specification (in terms of fate) and actual cytodifferentiation are usually separated in time, and modification of the position/distribution (of bristles in particular) does not affect the function of the organs Developmental compartmentalization of the conserved phylotypic stage Body plan is conserved and becomes evident at intermediate stage called the phylotypic stage. It is defined by a selector set of genes for transcription factors and secreted signals. The early path to the phylotypic stage in many phyla is often deconstrained, as well as later stages following it

Conservation and deconstraint Conserved processes deconstrain phenotypic variation and hence facilitate evolution Pre-Cambrian evolution selected core conserved mechanisms that were flexible, robust and versatile 1. Flexible and versatile proteins such as calmodulin readily impose inhibitions and activations on a number of targets 2. Weak linkage in information relay pathways 3. Exploratory systems like angiogenesis, nerve outgrowth, neural crest cells, MT-based morphogenesis are based on epigenetic variation and selection 4. Compartmentation includes genomic, which turn on and off groups of genes, spatial (body plan), which buffers against developmental inaccuracy and reduce pleiotropic damage from mutation. These properties facilitate evolutionary change by prserving viability when the size, anatomy or placement of cells changes and by allowing independent variation and selection in units smaller than the whole organism Evolvability has been selected in metazoan evolution