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Quantitative residue-level structure-evolution relationships in the yeast membrane proteome.

ABSTRACT: Membrane proteins exist in distinctly different environments than do soluble proteins, resulting in differences between their respective biophysical and evolutionary properties. In comparison with soluble proteins, relatively little is known about how the unique biophysical properties of membrane proteins affect their evolutionary properties at the residue level. In particular, transmembrane (TM) regions of membrane proteins tend to be more conserved than regions outside of the membrane (extramembrane [EM] regions), but the mechanisms underlying this phenomenon are not well understood. Here, we combine homology-based high-resolution three-dimensional protein models with rigorous evolutionary rate calculations to quantitatively assess residue-level structure-evolution relationships in the yeast membrane proteome. We find that residue evolutionary rate increases linearly with decreasing residue burial, regardless of the hydrophobic or hydrophilic nature of the solvent environment. This finding supports a direct relationship between a residue's selective constraint and the extent of its packing interactions with neighboring residues, independent of hydrophobic effects. Most importantly, for a fixed degree of burial, residues from TM regions tend to evolve more slowly than residues from EM regions. We attribute this difference to the increased importance of packing constraints and the decreased importance of hydrophobic effects in TM regions. This additional selective constraint on TM residues plays a dominant role in explaining why TM regions evolve more slowly than EM regions. In addition to revealing the universality of the linear relationship between residue burial and selective constraint across solvent environments, our work highlights the distinct residue-level evolutionary consequences imposed by the unique biophysical properties of the membrane environment.

SUBMITTER: Franzosa EA

PROVIDER: S-EPMC3641637 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Quantitative residue-level structure-evolution relationships in the yeast membrane proteome.

Franzosa Eric A EA Xue Ran R Xia Yu Y

Genome biology and evolution 20130101 4

Membrane proteins exist in distinctly different environments than do soluble proteins, resulting in differences between their respective biophysical and evolutionary properties. In comparison with soluble proteins, relatively little is known about how the unique biophysical properties of membrane proteins affect their evolutionary properties at the residue level. In particular, transmembrane (TM) regions of membrane proteins tend to be more conserved than regions outside of the membrane (extrame ...[more]

PMID: 23512408

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Project description:The crystal structures of the Ca(2+)- and H(+)-ATPases shed light into the membrane embedded domains involved in binding and ion translocation. Consistent with site-directed mutagenesis, these structures provided additional evidence that membrane-spanning segments M4, M5, M6 and M8 are the core through which cations are pumped. In the present study, we have used alanine/serine scanning mutagenesis to study the structure-function relationships within M6 (Leu-721-Pro-742) of the yeast plasma membrane ATPase. Of the 22 mutants expressed and analyzed in secretory vesicles, alanine substitutions at two well conserved residues (Asp-730 and Asp-739) led to a complete block in biogenesis; in the mammalian P-ATPases, residues corresponding to Asp-730 are part of the cation-binding domain. Two other mutants (V723A and I736A) displayed a dramatic 20-fold increase in the IC(50) for inorganic orthovanadate compared to the wild-type control, accompanied by a significant reduction in the K(m) for Mg-ATP, and an alkaline shift in the pH optimum for ATP hydrolysis. This behavior is apparently due to a shift in equilibrium from the E(2) conformation of the ATPase towards the E(1) conformation. By contrast, the most striking mutants lying toward the extracellular side in a helical structure (L721A, I722A, F724A, I725A, I727A and F728A) were expressed in secretory vesicles but had a severe reduction of ATPase activity. Moreover, all of these mutants but one (F728A) were unable to support yeast growth when the wild-type chromosomal PMA1 gene was replaced by the mutant allele. Surprisingly, in contrast to M8 where mutations S800A and E803Q (Guerra et al., Biochim. Biophys. Acta 1768: 2383-2392, 2007) led to a dramatic increase in the apparent stoichiometry of H(+) transport, three substitutions (A726S, A732S and T733A) in M6 showed a reduction in the apparent coupling ratio. Taken together, these results suggest that M6 residues play an important role in protein stability and function, and probably are responsible for cation binding and stoichiometry of ion transport as suggested by homology modeling.

Dataset Information

Quantitative residue-level structure-evolution relationships in the yeast membrane proteome.

Publications

Quantitative residue-level structure-evolution relationships in the yeast membrane proteome.

Similar Datasets

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