Curr Opin Struct Biol 1998 Jun;8(3):380-387
How far divergent evolution goes in proteins.
Centre for Protein Engineering, MRC Centre, Cambridge, UK. firstname.lastname@example.org
[Medline record in process]
In theory, mutations of protein sequences may eventually generate different functions as well as different structures. The observation of such records of protein evolution have been obscured by the dissipation of memory about the ancestors. In the past year, new advances in our understanding of divergent evolution were allowed by new protein structure determinations, including the ClpP proteases, steroid delta-isomerase, carboxypeptidase G2, the thrombin inhibitor triabin and the chloroplast Rieske protein. There is strong evidence for their distant homology with proteins of known structure despite significant functional or structural differences.
PMID: 9666335, UI: 98330764
Cell Mol Life Sci 1997 Sep;53(9):701-730
Molecular mechanisms of thrombin function.
Di Cera E, Dang QD, Ayala YMDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA. email@example.com
The discovery of thrombin as a Na(+)-dependent allosteric enzyme has revealed a novel strategy for regulating protease activity and specificity. The alllosteric nature of this enzyme influences all its physiologically important interactions and rationalizes a large body of structural and functional information. For the first time, a coherent mechanistic framework is available for understanding how thrombin interacts with fibrinogen, thrombomodulin and protein C, and how Na+ binding influences the specificity sites of the enzyme. This information can be used for engineering thrombin mutants with selective specificity towards protein C and for the rational design of potent active site inhibitors. Thrombin also serves as a paradigm for allosteric proteases. Elucidation of the molecular basis of the Na(+)-dependent allosteric regulation of catalytic activity, based on the residue present at position 225, provides unprecedented insights into the function and evolution of serine proteases. This mechanism represents one of the simplest and most important structure-function correlations ever reported for enzymes in general. All vitamin K-dependent proteases and some complement factors are subject to the Na(+)-dependent regulation discovered for thrombin. Na+ is therefore a key factor in the activation of zymogens in the coagulation and complement systems.
Ciba Found Symp 1997;212:4-17
Evolution of vertebrate fibrin formation and the process of its dissolution.
Doolittle RF, Spraggon G, Everse SJCenter for Molecular Genetics, University of California at San Diego, La Jolla 92093-0634, USA.
The thrombin-catalysed conversion of fibrinogen into a fibrin gel is common to all extant vertebrates. Because fibrin formation is both temporary and risky, an effective scheme for fibrinolysis evolved concomitantly. In this regard, the fibrinogen molecule is well adapted both for network polymerization and for subsequent dismantling. The question is, has it always been so? It has long been known that the three non-identical chains that compose vertebrate fibrinogen are descended from a common ancestor, and the original molecule must have been either a homotrimer or a dimer thereof. Three-dimensional studies on core fragments of fibrinogen are revealing new insights about both fibrin formation and its destruction. These studies are also showing exactly what structural changes have accompanied changes in function for the various domains. Chief among these is the reversal of direction for the alpha chain after replacement of its C-terminal domain.