A limited universe of membrane protein families and folds

Oberai, Amit; Ihm, Yungok; Kim, Sanguk; Bowie, James U.

doi:10.1110/ps.062109706

Cited by 83 publications

(76 citation statements)

References 65 publications

(89 reference statements)

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“…To make good use of dispersion forces and polar interactions, membrane proteins therefore may need to pack a larger fraction of their surface area to maintain a stable structure. Regardless of the reason for additional packing, this physical constraint seems to be important for disease etiology and could be a factor in the smaller number of integral-membrane protein families that seem to exist compared with water-soluble protein families (21,22). It has been suggested that water-soluble proteins evolved from the extramembrane segments of primordial membrane proteins (23).…”

Section: Resultsmentioning

confidence: 99%

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Oberai

Joh

Pettit

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The amino acid sequences of transmembrane regions of helical membrane proteins are highly constrained, diverging at slower rates than their extramembrane regions and than water-soluble proteins. Moreover, helical membrane proteins seem to fall into fewer families than water-soluble proteins. The reason for the differential restrictions on sequence remains unexplained. Here, we show that the evolution of transmembrane regions is slowed by a previously unrecognized structural constraint: Transmembrane regions bury more residues than extramembrane regions and soluble proteins. This fundamental feature of membrane protein structure is an important contributor to the differences in evolutionary rate and to an increased susceptibility of the transmembrane regions to disease-causing single-nucleotide polymorphisms.disease mutation ͉ potassium channel ͉ protein folding ͉ protein stability ͉ single nucleotide polymorphisms E volutionary rates vary considerably in different cellular compartments (1). Membrane proteins have been found to diverge faster overall than soluble proteins (2, 3), but this increased rate is confined entirely to the rapidly evolving extramembrane regions. Transmembrane regions, on average, diverge much more slowly than the extramembrane regions more slowly than soluble proteins (1, 4-6).A major factor controlling protein sequence divergence is the need to preserve protein function by maintaining a folded structure (7). Because the physical forces that drive folding can change with environment, proteins in different cellular locations can be subject to distinct evolutionary constraints. Membrane proteins, in particular, must accommodate to a dramatically varied environment, ranging from hydrocarbon chains in the bilayer core to water as they emerge from the membrane (8, 9). It therefore seems possible that distinct structural imperatives found in different environments could be an important contributor to evolutionary rates. An obvious sequence adaptation is the hydrophobic matching of the protein exterior, reflected in an apolar transmembrane amino acid composition. Although amino acid diversity is more limited in the transmembrane segments, simple compositional differences do not explain the slower divergence rates of transmembrane regions (1, 4, 5).Here, we find that the transmembrane regions of membrane proteins bury more residues on average than soluble proteins and much more than extramembrane regions, a possible mechanism for increasing stabilization in the absence of the hydrophobic effect. Because buried residues evolve at slower rates than surface residues (10-12), the higher level of residue burial in the transmembrane regions leads to slower sequence divergence. Moreover, we find that higher residue burial may explain a higher prevalence of disease-causing mutations in the transmembrane region of membrane proteins compared with the extramembrane regions. Results and DiscussionTransmembrane Regions Bury More Residues. Fig. 1A shows plots of the fractional surface area buried per residue v...

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Section: Resultsmentioning

confidence: 99%

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Oberai

Joh

Pettit

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Although this coverage may seem limiting, results from the Protein Structure Initiative suggest that Ϸ90% of this unannotated space is comprised of variants of already discovered fold families (20), and that only 10% of the undiscovered fold families will actually be metalbinding (21). It appears that membrane proteins are similarly distributed, with the most abundant membrane folds being already described (22). Essentially, it seems unlikely that a new protein fold family will be discovered that is abundant enough to overly skew the observed results.…”

Section: Resultsmentioning

confidence: 99%

Modern proteomes contain putative imprints of ancient shifts in trace metal geochemistry

Dupont

Yang²,

Palenik³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

212

106

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Because of the rise in atmospheric oxygen 2.3 billion years ago (Gya) and the subsequent changes in oceanic redox state over the last 2.3-1 Gya, trace metal bioavailability in marine environments has changed dramatically. Although theorized to have influenced the biological usage of metals leaving discernable genomic signals, a thorough and quantitative test of this hypothesis has been lacking. Using structural bioinformatics and whole-genome sequences, the Fe-, Zn-, Mn-, and Co-binding metallomes of 23 Archaea, 233 Bacteria, and 57 Eukarya were constructed. These metallomes reveal that the overall abundances of these metalbinding structures scale to proteome size as power laws with a unique set of slopes for each Superkingdom of Life. The differences in the power describing the abundances of Fe-, Mn-, Zn-, and Co-binding proteins in the proteomes of Prokaryotes and Eukaryotes are similar to the theorized changes in the abundances of these metals after the oxygenation of oceanic deep waters. This phenomenon suggests that Prokarya and Eukarya evolved in anoxic and oxic environments, respectively, a hypothesis further supported by structures and functions of Fe-binding proteins in each Superkingdom. Also observed is a proliferation in the diversity of Zn-binding protein structures involved in protein-DNA and protein-protein interactions within Eukarya, an event unlikely to occur in either an anoxic or euxinic environment where Zn concentrations would be vanishingly low. We hypothesize that these conserved trends are proteomic imprints of changes in trace metal bioavailability in the ancient ocean that highlight a major evolutionary shift in biological trace metal usage.bioinorganic chemistry ͉ evolution ͉ fold families ͉ structural bioinformatics T he emergence of oxygenic photosynthesis is associated with major changes in global biogeochemistry and metabolism (1, 2). In particular, the rise in atmospheric oxygen Ϸ2.3 billion years ago (Gya) (3, 4) potentially led to the oxygenation of the entire ocean (5), whereas an alternative theory proposes that the deep ocean became euxinic (anoxic and sulfidic) Ϸ1.8 Gya (6, 7), before an oxygenation of deep waters Ϸ1 Gya (8). Putting aside for now when and where, these changes in the overall redox state of the ocean would dramatically influence trace metal chemistry and bioavailability, with an anoxic ocean being characterized by relatively high Fe, Mn, and Co but low Zn concentrations (9) (Fig. 4, which is published as supporting information on the PNAS web site). A euxinic ocean would have comparatively lower concentrations of all of these metals, particularly Zn (9) (Fig. 4). The oxygenation of oceanic deep waters would have dramatically increased Zn concentrations, with concomitant yet less severe decreases in Fe, Mn, and Co levels (9) (Fig. 4). As postulated by Williams and Frausto da Silva (10), these drastic shifts in metal bioavailability theoretically influenced the selection of trace elements for biological usage, leaving a record within the genomes and proteomes ...

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“…To assess the effect these mutations might have on the folded structure and to provide evidence that the deduced structure of Sod2 TM IV is valid, we constructed a homology model of the membrane domain of Sod2. Mounting evidence suggests that a finite number of folds exist for membrane transporters (63) and that proteins with quite different primary amino acid sequences can have surprisingly similar structures. For example, the bile acid sodium symporter of Neisseria meningitides has a low primary sequence identity to E. coli NhaA, but the structure is surprisingly similar to that of NhaA (59).…”

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confidence: 99%

Structural and Functional Analysis of Transmembrane Segment IV of the Salt Tolerance Protein Sod2*

Ullah

Kemp

Lee

et al. 2013

Journal of Biological Chemistry

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A limited universe of membrane protein families and folds

Cited by 83 publications

References 65 publications

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Structural imperatives impose diverse evolutionary constraints on helical membrane proteins

Modern proteomes contain putative imprints of ancient shifts in trace metal geochemistry

Structural and Functional Analysis of Transmembrane Segment IV of the Salt Tolerance Protein Sod2*

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