Structural genomics on membrane proteins

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For example the recombinant production of many membrane proteins is a major challenge and purification and crystallization are also difficult steps. The result: although around 25 percent of all proteins are membrane proteins, they account for less than one percent of the total number of proteins with known structures.

Membrane protein structures are thus underrepresented fold. Given their medical relevance, they should be much better known.

Protein overexpression

Since the experimental analysis of a membrane protein can take up to several years, the NYCOMPS scientists applied a bioinformatics strategy, the so-called homology modeling. The basic assumption of this strategy is that proteins with common evolutionary predecessors resemble each other in their amino acid sequences, as well as in their three-dimensional structure. If the structure of one of the related proteins can be determined experimentally, the remaining ones can be predicted. In the case of the bacterial membrane protein TehA they could bring all pieces of the puzzle together.

Using a multistage selection process we chose 43 proteins from 38 different organisms," says TUM computational biologist Marco Punta. Scientists at Columbia University now succeeded in experimentally determining the tertiary structure of the membrane protein TehA of the bacterium Haemophilus influenzae using X-ray crystallography. With a resolution of 0. Furthermore, the experiment harbored a surprise: The TehA membrane protein has a hitherto entirely unknown fold. After getting to know the "TehA family," the scientists at Columbia University succeeded in deriving the structures of the individual proteins.

In particular, they modeled the structure of the plant membrane protein SLAC1. Comparing this to the protein structure of TehA derived experimentally, they could build a structural model for SLAC1 -- entirely without experimentation, using nothing but bioinformatics methods. The results at hand show that this strategy can work for membrane proteins, too," says Burkhard Rost. Ultimately, the three-dimensional structures are determined to identify the function of the proteins using mutagenesis tests.

Although the membrane proteins TehA and SLAC1 are only distantly related -- the overlap of the amino acid sequence is only 19 percent -- the predicted tertiary structure of SLAC1 was so good that a new hypothesis on the function of the SLAC1 membrane protein could be put forward. SLAC1 is found in the stomata of the plant Arabidopsis thaliana. Stomata control the exchange of water vapor and carbon dioxide between the plant and its environment.

This is very important in photosynthesis. The membrane protein SLAC1 plays a role in this process, as well, as part of the anion channel: It influences the turgor pressure -- the pressure of cell fluid on the cell wall -- and thus the gas exchange of the plant cell as a reaction to environmental influences such as aridity and high carbon dioxide concentration.

Coordinating the impact of structural genomics on the human α-helical transmembrane proteome

SLAC1 anion channels are entirely novel in structure and, apparently, in the mechanism for ion conductance. The SLAC1 pore has a relatively uniform diameter, but in the middle a Phenylalanine-group blocks the way. The results suggest that this amino acid is turned away when the ion channel is activated through binding of a triggering protein.

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A high-throughput platform for structural genomics of integral membrane proteins

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Structural Genomics on Membrane Proteins

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The Structural Genomics Consortium

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Structural Genomics on Membrane Proteins: 1st Edition (Paperback) - Routledge

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Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins
Structural genomics on membrane proteins Structural genomics on membrane proteins

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