Douglas Freymann


PhD, Harvard University

Molecular Pharmacology and Biological Chemistry
Driskill Graduate Program

Office Phone: 312.503.1877
Lab Phone: 312.503.4273
Email
Freymann Lab

Research

Structural Biology of the SRP GTPases: The Signal Recognition Particle (SRP) co-translational protein targeting pathway is conserved through evolution and plays a fundamental role in the biology of cells. SRP binds to the translating ribosome, recognizing the signal peptide of the emerging polypeptide and targeting it to a membrane-associated receptor. The SRP is a ribonucleoprotein which, in prokaryotes, comprises the 4.5S RNA and the protein Ffh. Its receptor, in prokaryotes a protein called FtsY, is a structural homolog of Ffh. Both Ffh and FtsY are GTPases - they interact directly to assemble the SRP targeting complex at the membrane.

Our laboratory is studying the structural basis for regulation of the assembly and disengagement of these two GTPases, Ffh and FtsY. The SRP GTPases are structurally similar to other well-known members of the GTPase superfamily, such as Ras, Ran, and the Ga subunits of the heterotrimeric G-proteins. In each of these proteins, GTP binding, hydrolysis, and exchange regulate, and are regulated by, binding other macromolecular components of the cell, thereby constituting elements of the interaction pathways that mediate signal transduction and assembly.

The structures of the SRP GTPases Ffh and FtsY have suggested new mechanisms by which function can be elaborated from a common GTPase fold. The structure of the heterodimeric complex of Ffh and FtsY was determined in our laboratory in 2003. It revealed a remarkably symmetric 'homo'heterodimer assembly mechanism that directly couples the active sites of the two proteins. We are now focusing on understanding the structural basis for regulation of the two SRP GTPases, using high resolution X-ray crystallographic studies of the nucleotide-bound Ffh and biochemical, biophysical and crystallographic studies of the assembly of the Ffh:FtsY targeting complex.

The long term aims are to understand the specific role of the two SRP GTPases in the biology of the cell, and to understand the general principles by which the protein architecture of the GTPase fold provides means for diverse members of the GTPase superfamily to play critical roles in the transduction of cellular signals and the assembly of macromolecular complexes.

Publications

Focia, P.J., Shepotinovskaya, I.V., Seidler, J.A., & Freymann, D.M. Heterodimeric GTPase core of the SRP targeting complex. Science 303 373-377 (2004)
Abstract

Focia, P.J., Gawronski-Salerno, J., Coon, J.S. V, & Freymann, D.M. Structure of a GDPAlF4 complex of the SRP GTPases Ffh and FtsY, and identification of a peripheral nucleotide interaction site. J. Mol Biol. 360 631-643 (2006)

Gawronski-Salerno, J., Coon V, J.S., Focia, P.J. & Freymann D.M. X-ray structure of the T. aquaticus FtsY:GDP complex suggests functional roles for the C-terminal helix of the SRP GTPases. Proteins: Struct. Funct. Bioinf. In press (2006)

Focia, P.J., Alam, H., Lu, T., Ramirez, U.D., & Freymann, D.M. Novel Protein and Mg2+ Configurations in the Mg2+GDP Complex of the SRP GTPase Ffh. Proteins54 222-230 (2004)

Shepotinovskaya, I.V., Focia, P.J., & Freymann, D.M. Crystallization of the GMPPCP complex of the NG domains of T. aquaticus Ffh and FtsY.Acta Cryst. D591834-1837 (2003)

Links

PubMed Reference Lookup

Recent Photos

April 16, 2015