Overview
Research in our lab aims at understanding protein function on the basis of atomic structure determination using x-ray crystallography as the main tool. One focal point is the elucidation of the structure of the nuclear pore complex, an elaborate macromolecular protein assembly that constitutes the only gateway into and out of the eukaryotic cell nucleus. A second area of interest centers on the regulation of protein transport across the membrane of the endoplasmic reticulum, a process that relies on the concerted action of three G proteins. We employ an integrative approach to these research areas combining structure determination with biochemical, biophysical and cell biological methods.

Research Summary
The nuclear pore complex: In eukaryotes, genes are transcribed from DNA into RNA in the nucleus, whereas proteins are synthesized in the cytoplasm. Therefore, traffic across the nuclear envelope membrane is heavy and fundamentally important. Our goal is to understand the mechanism of nucleo-cytoplasmic transport of proteins and RNA. Nuclear pore complexes (NPCs) are vast protein assemblies that form circular openings in the nuclear envelope and are the only known entry and exit site of the nucleus. Composed of multiple copies of roughly 30 different proteins, organized in distinct subcomplexes, the entire NPC constitutes one of the largest known protein assemblies in the cell (roughly 16 times the size of a ribosome). Our long-term objective is to elucidate the entire NPC structure in atomic detail. As a start, we are characterizing the subcomplexes from which the NPC is built and into which it disintegrates during the breakdown of the nuclear envelope when the cell divides. These subcomplexes are amenable to high-resolution crystallographic analysis. Resulting structures will allow for much more precise functional probing of nucleo-cytoplasmic transport than currently possible.

Regulation of protein import into the endoplasmic reticulum: Transport into the endoplasmic reticulum (ER), a cavernous extended inner membrane system of eukaryotes, constitutes the first sorting step of any eukaryotic protein that is destined for secretion. The process involves a ribosome engaged in the synthesis of a secretory protein, the signal recognition particle (SRP) which targets the ribosome to the ER membrane via interaction with its cognate receptor SR, and a protein conducting channel that facilitates the passage of the nascent polypeptide through the ER membrane. Correct timing of events is crucial and thus tightly regulated by three G proteins that function as molecular switches. We have recently solved the crystal structure of one of these switches, the beta-subunit of the heterodimeric SRP receptor in complex with its interaction domain of the alpha-subunit. Current research is focused on elucidating additional snapshots of SR in complex with its partners in order to fully understand the regulatory role of each of the G proteins. In addition to ER targeting we ask whether evolutionary related regulatory circuitry might be used in other cellular processes as well.

Selected Publications
Schwartz, T.U. Modularity within the Architecture of the Nuclear Pore Complex. Curr. Op. Struct. Biol., 15, 221-226. (2005).

Berke, I.C., Boehmer, T., Blobel, G. & Schwartz, T.U. Structural and Functional Analysis of Nup133 Domains Reveals Modular Building Blocks of the Nuclear Pore Complex. J. Cell Biol., 167, 591-597. (2004).

Schwartz, T.U., Walczak, R. & Blobel, G. Circular Permutation as a Tool to Reduce Surface Entropy Triggers Crystallization of the Signal Recognition Particle Receptor β-Subunit. Protein Sci., 13, 2814-2818. (2004).

Helmers, J., Schmidt, D., Glavy, J.S., Blobel, G. & Schwartz, T. The β-Subunit of the Protein-Conducting Channel of the Endoplasmic Reticulum Functions as the Guanine Nucleotide Exchange Factor for the b-Subunit of the Signal Recognition Particle Receptor. J. Biol. Chem., 278, 23686-23690. (2003).

Schwartz, T. & Blobel, G. Structural Basis for the Function of the β-Subunit of the Eukaryotic Signal Recognition Particle Receptor. Cell, 112, 793-803. (2003).

Schwartz, T., Behlke, J., Lowenhaupt, K., Heinemann, U. & Rich, A. Structure of the DLM-1—Z-DNA complex reveals a conserved family of Z-DNA-binding proteins. Nat. Struct. Biol., 8, 761-765. (2001).

Schwartz, T., Rould, M.A., Lowenhaupt, K., Herbert, A. & Rich, A. Crystal Structure of the Zα Domain of the Human Editing Enzyme ADAR1 Bound to Left-Handed Z-DNA. Science 284, 1841-1845. (1999).

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