Dataset Information

Substitution rates in alpha-helical transmembrane proteins.

ABSTRACT: It has been shown previously that some membrane proteins have a conserved core of amino acid residues. This idea not only serves to orient helices during model building exercises but may also provide insight into the structural role of residues mediating helix-helix interactions. Using experimentally determined high-resolution structures of alpha-helical transmembrane proteins we show that, of the residues within the hydrophobic transmembrane spans, the residues at lipid and subunit interfaces are more evolutionarily variable than those within the lipid-inaccessible core of a polypeptide's transmembrane domain. This supports the idea that helix-helix interactions within the same polypeptide chain and those at the interface between different polypeptide chains may arise in distinct ways. To show this, we use a new method to estimate the substitution rate of an amino acid residue given an alignment and phylogenetic tree of closely related proteins. This method gives better sensitivity in the otherwise-conserved transmembrane domains than a conventional similarity analysis and is relatively insensitive to the sequences used.

SUBMITTER: Stevens TJ

PROVIDER: S-EPMC2374033 | biostudies-literature | 2001 Dec

REPOSITORIES: biostudies-literature

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Substitution rates in alpha-helical transmembrane proteins.

Stevens T J TJ Arkin I T IT

Protein science : a publication of the Protein Society 20011201 12

It has been shown previously that some membrane proteins have a conserved core of amino acid residues. This idea not only serves to orient helices during model building exercises but may also provide insight into the structural role of residues mediating helix-helix interactions. Using experimentally determined high-resolution structures of alpha-helical transmembrane proteins we show that, of the residues within the hydrophobic transmembrane spans, the residues at lipid and subunit interfaces a ...[more]

PMID: 11714918

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Project description:Membrane proteins, particularly those that are α-helical, such as transporters and G-protein-coupled receptors (GPCRs), have significant biological relevance. However, their expression and purification pose difficulties because of their poor water solubilities, which impedes progress in this field. The QTY method, a code-based protein-engineering approach, was recently developed to produce soluble transmembrane proteins. Here, we describe a comprehensive Web server built for QTY design and its relevance for in silico analyses. Typically, the simple design model is expected to require only 2 to 4 min of computer time, and the library design model requires 2 to 5 h, depending on the target protein size and the number of transmembrane helices. Detailed protocols for using the server with both the simple design and library design modules are provided. Methods for experiments following the QTY design are also included to facilitate the implementation of this approach. The design pipeline was further evaluated using microbial transmembrane proteins and structural alignment between the designed proteins and their origins by employing AlphaFold2. The results reveal that mutants generated by the developed pipeline were highly identical to their origins in terms of three-dimensional (3D) structures. In summary, the utilization of our Web server and associated protocols will enable QTY-based protein engineering to be implemented in a convenient, fast, accurate, and rational manner. The Protein Solubilizing Server (PSS) is publicly available at http://pss.sjtu.edu.cn. IMPORTANCE Water-soluble expression and purification are of considerable importance for protein identification and characterization. However, there has been a lack of an effective method for water-soluble expression of membrane proteins, which has severely hampered their studies. Here, an enabling comprehensive Web server, PSS, was developed for designing water-soluble mutants of α-helical membrane proteins, based on QTY design, a code-based protein-engineering approach. With microbial transmembrane proteins and GPCRs as examples, we systematically evaluated the server and demonstrated its successful performance. PSS is readily available for worldwide users as a Web-based tool, rendering QTY-based protein engineering convenient, efficient, accurate, and rational.

Dataset Information

Substitution rates in alpha-helical transmembrane proteins.

Publications

Substitution rates in alpha-helical transmembrane proteins.

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