Center for Infectious Disease and Vector Research

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CEPCEB- Student's Special Seminar

W. Ross Ellington, Ph.D.

Friday, April 5, 2013
Noon1 p.m.


Genomics Building , Genomics Auditorium RM 1102A
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W. Ross Ellington, Ph.D.
Associate Vice President for Research
Michael J. Greenberg Professor of Biological Science
Florida State University

Title: Cell Motility, Reaction-Diffusion Constraints and the Origin and Divergence of the Creatine Kinase Enzyme Family

Mitochondrial oxidative phosphorylation maintains the ATP hydrolysis reaction displaced far from thermodynamic equilibrium. As a consequence, the effective free energy of ATP hydrolysis (DGATP) approaches -60 kJ mol-1 or higher in many cell types. Temporal and spatial mismatches of ATP supply and demand could potentially produce catastrophic reductions in DGATP. Phosphagen kinase reactions (phosphagen MgADP ß à guanidino acceptor MgATP) mitigate such mismatches by buffering the DGATP at values consistent with physiological function. A diverse array of eight different phosphagen kinases and corresponding phosphagens is present in animals. The most widely distributed and well studied of these are the arginine kinase (AK)/phosphoarginine (PA) and creatine kinase (CK)/phosphocreatine (PC) systems. AKs are typically monomeric, cytoplasmic proteins while CKs are present as a family of isoforms that are functional oligomers targeted to different intracellular compartments- cytoplasmic (CytCK), mitochondrial (MtCK) and flagellar (FlgCK). Conventional wisdom supports the view that CK evolved fairly recently from an ancestral AK-like protein. However, it is now clear that the system of CK isoforms actually has a rather ancient evolutionary history. All three CKs are present in higher and lower invertebrates. Sponges, which constitute the most primitive group of living multi-cellular animals, express CytCKs, MtCKs and FlgCKs. Chaonoflagellates, the closest, extant protozoan sister group of metazoans, have oligomeric AKs that appear to have evolved secondarily from a CK-like ancestor. Furthermore, recent genomic/EST sequences and some new experimental data have shown that CKs and homologues of the enzymes of creatine biosynthesis are present in several alveolate protozoans. The earliest eukaryotic cells are thought to have crawled or glided across solid surfaces and possessed a single flagellum used in food acquisition. A key event in eukaryotic evolution was the transition to a free swimming state in which the flagellum became a locomotory structure. ATP turnover by dynein ATPases and resistance to diffusion of adenine nucleotides from the mitochondria to the end of the flagella created large reaction-diffusion constraints. The CK isoform system likely evolved at the dawn of the radiation of the eukaryotes to mitigate spatial mismatches of ATP supply and demand in these early motile cells. This ancient heritage is reflected in a broad range of invertebrates in which other phosphagen systems are found in somatic cells and eggs but the CK/PC system is consistently present in highly motile primitive-type spermatozoa. Expression of cytoplasmic and mitochondrial CK isoforms in somatic tissues seems to be correlated with the advent of well-defined tissues and organs, especially neuromuscular systems. A genome duplication event early in the evolution of vertebrates resulted in two copies each of the CytCK and MtCK genes. Subsequent divergence of these genes led to tissue specific isoforms- muscle (M) and brain (B) type CytCKs and sarcomeric and ubiquitous MtCKs. Further evolutionary changes in the catalytic properties of these proteins matched the physiological context in which they function. Additional structural elements were acquired to facilitate intracellular localization such as in the case of the binding of M-CytCKs to the myofibril and sarcoplasmic reticulum. The available evidence suggests that the CK/PC system is ancient. Its origin can be linked to spatial energy mismatches associated with motility and the polarized morphology of early eukaryotic cells. The evolution of CK isoforms targeted to different intracellular compartments and fine-tuning of the capacity for localization at specific sites greatly enhanced both the spatial and temporal DGATP buffering roles of the CK/PC system as exemplified in the various cell types of mammals.


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