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Journal of Bacteriology, February 2001, p. 1012-1021, Vol. 183, No. 3
0021-9193/01/$04.00+0 DOI: 10.1128/JB.183.3.1012-1021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Size Comparisons among Integral Membrane Transport
Protein Homologues in Bacteria, Archaea,
and Eucarya
Yong Joon
Chung,
Christel
Krueger,
David
Metzgar, and
Milton H.
Saier Jr.*
Department of Biology, University of
California at San Diego, La Jolla, California 92093-0116
Received 7 July 2000/Accepted 3 November 2000
 |
ABSTRACT |
Integral membrane proteins from over 20 ubiquitous families of
channels, secondary carriers, and primary active transporters were
analyzed for average size differences between homologues from the three
domains of life: Bacteria, Archaea, and
Eucarya. The results showed that while eucaryotic
homologues are consistently larger than their bacterial counterparts,
archaeal homologues are significantly smaller. These size differences
proved to be due primarily to variations in the sizes of hydrophilic
domains localized to the N termini, the C termini, or specific loops
between transmembrane 
-helical spanners, depending on the family.
Within the Eucarya domain, plant homologues proved to be
substantially smaller than their animal and fungal counterparts. By
contrast, extracytoplasmic receptors of ABC-type uptake systems in
Archaea proved to be larger on average than those of their
bacterial homologues, while cytoplasmic enzymes from different
organisms exhibited little or no significant size differences. These
observations presumably reflect evolutionary pressure and
molecular mechanisms that must have been operative since these
groups of organisms diverged from each other.
| |
INTRODUCTION |
The three largest classes of
transporters found in nature are channels, secondary carriers, and
primary active transporters (8, 10). Channel proteins
facilitate passive diffusion of their substrates across membranes
through aqueous pores, while secondary carriers generally utilize
electrochemical gradients of H+, Na+, and
solutes to drive the active accumulation or efflux of their primary
substrates, and primary active transporters couple transport to the
expenditure of a primary source of energy such as ATP hydrolysis or
electron flow (10, 16). While channel proteins frequently span the membrane only a few times and form oligomeric complexes, secondary carriers and primary active transporters span the membrane multiple times and usually function as monomers or dimers in the absence of accessory proteins (4). Higher complexes of
primary and secondary active transporters can provide regulatory
(7, 11) or targeting and stability functions
(15).
Recently we have classified transport proteins according to a
functional and phylogenetic system called the transporter
classification (TC) system (8-10). While many of the
identified families of transport proteins are found in only one of the
three domains of living organisms (Bacteria,
Archaea, or Eucarya), others are ubiquitous, being found in all three domains. Our studies have led to the conclusion that these ubiquitous families are ancient families that
existed prior to the divergence of Eucarya and
Archaea from Bacteria and that little horizontal
transfer of genetic material encoding transport proteins between these
three domains of life has occurred at least during the past 2 to 3 billion years (8, 9).
In this study we compared the sizes of homologues of the ubiquitous
families in the three domains of living organisms. We showed that while
the eucaryotic homologues are consistently larger than their bacterial
counterparts, the archaeal homologues are almost always smaller.
Moreover, within the Eucarya domain, plant homologues are
consistently smaller than the fungal and animal homologues, which are
of similar sizes. These observations apparently do not apply to
extracellular receptors and cytoplasmic enzymes, which exhibit the
reverse size tendencies or no significant differences. The size
differences observed for secondary carriers of homologues from the
three domains of life proved to be due primarily to variations in the
sizes of specific hydrophilic domains within these proteins, and the
locations of these size-variable domains appear to be characteristic of
specific families.
| |
MATERIALS AND METHODS |
The PSI-BLAST database search method
(http://www.ncbi.nlm.nih.gov/blast/psiblast.cgi) was used to
identify homologous proteins. Multiple alignments were generated using
the CLUSTAL X program (13), and hydropathy and putative
transmembrane spanner (TMS) analyses were conducted using the TMPred
program (2). Positions of size variation among homologues
were identified using a combination of programs for multiple alignment
(CLUSTAL X) and topological analysis (TMPred). To test for
statistically significant differences in protein length, the data were
analyzed using two-tailed Sign tests (17).
| |
RESULTS |
Size variation in integral membrane transport protein homologues in
Bacteria, Archaea, and
Eucarya.
Table 1
presents the average sizes, in numbers of amino acyl residues, of the
integral membrane protein homologues of 15 families of secondary
carriers, 3 families of channel proteins, and 4 families of primary
active transporters present in the archaeal, bacterial, and eucaryotic
domains. The number of homologues examined is presented in parentheses.
The average sizes of the archaeal and eucaryotic homologues relative to
the average sizes of the bacterial proteins are also provided. All of
the archaeal homologues available in the SwissProt, GenBank, and PIR
databases at the time these studies were conducted were included in the
analysis. When limited numbers of bacterial or eucaryotic homologues
comparable to the number of archaeal proteins were identified, all of
these were also included. However, when the numbers of bacterial and/or eucaryotic homologues considerably exceeded the number of archaeal family members, several proteins from the former two groups were generally selected at random from various organisms. In some cases, many eucaryotic proteins were included so that proteins within specific
Eucarya kingdoms (animals, plants, and fungi) could be compared (see below).
Examination of the results presented in Table
1 reveals that of the 22 protein families studied, the average sizes of the
eucaryotic
homologues are always substantially greater than those
of the
procaryotic homologues. Moreover, with only three exceptions
(the amino
acid-polyamine-organocation [APC] and formate-nitrite
transporter
[FNT] families of secondary carriers and the SecY
proteins of the
type II protein secretion pathway family of primary
active protein
secretory systems), the average sizes of the archaeal
homologues are
always less than those of the bacterial
homologues.
All of the size difference values, obtained when the archaeal or
eucaryotic homologues for the various families were compared
with the
bacterial homologues (Table
1), were averaged. The average
archaeal
protein size for all 22 families examined was 92% of
that of the
bacterial homologues, while the average eucaryotic
protein size for all
20 families examined was 140% of that of
the bacterial homologues.
Thus, while the archaeal proteins are
8% smaller than the bacterial
proteins, on average, the eucaryotic
proteins are 40%
larger.
Size variation in integral membrane transport protein homologues in
fungi, plants, and animals.
Within the Eucarya domain,
animal, plant, and fungal (including yeast) homologues were analyzed
separately (Table 2). In all but three of
the families of transport proteins analyzed, the plant proteins
exhibited average sizes that were substantially smaller than the animal
or fungal homologues. The exceptions were the sugar porter family of
the major facilitator superfamily, the ammonium transporter family, and
the SecY family within type II protein secretion pathway systems. In
the sugar porter family of the major facilitator super family, animal
homologues proved to be slightly smaller on average than the plant
homologues.
All of the size difference values, obtained when the animal or plant
homologues for the various families were compared with
the fungal
homologues (Table
2), were averaged. The average animal
protein size
for all 14 families examined was 105% of that of
the fungal
homologues, while the average plant protein size for
the 13 families
examined was 83% of that of the fungal homologues.
Thus, while the
animal proteins are 5% larger than the fungal
proteins, on
average, the plant proteins are 17%
smaller.
Size variation in homologous constituents of the ABC-type transport
system in Bacteria and Archaea.
The ABC
superfamily of uptake permeases is restricted to procaryotes, but it is
found in both Bacteria and Archaea. These systems
include three constituents: extracytoplasmic receptors, integral
membrane proteins, and cytoplasmic ATP-hydrolyzing constituents. Over
20 families of these systems have been identified (10). These types of homologues (receptors, integral membrane constituents, and cytoplasmic ATP-hydrolyzing energizers) were analyzed for size
variation (see Tables 3, 4, and 5,
respectively). As shown in Table 3, the average archaeal receptor sizes
proved to be greater than those of the average bacterial receptor sizes
for 11 of the 13 families that have homologues in both domains.
Overall, the archaeal receptors are 7% larger, on average, than their
bacterial homologues. By contrast, the integral membrane archaeal
homologues of ABC systems are usually smaller than the bacterial
homologues (Table 4). Thus, of the 20 families examined, 15 proved to have smaller archaeal homologues, on
average, than bacterial homologues. The average size difference proved
to be 3.5%. Finally, the cytoplasmic ATP-hydrolyzing energizers tend
to be somewhat smaller in Archaea than in
Bacteria (Table 5). Thus, of
the 16 families analyzed, 13 were smaller and 3 were larger, on
average. Overall, the archaeal cytoplasmic proteins were 3.5% smaller
than their bacterial homologues. Thus, the trend displayed by the ABC
membrane proteins (Table 4) agreed with that for other integral
membrane transport proteins (Table 1). The size differences for the
archaeal extracytoplasmic receptors were opposite to that observed for
the integral membrane constituents, with the archaeal receptors being
substantially larger than their bacterial homologues. The
ATP-hydrolyzing energizers showed minimal size differences.
Size variation in homologous cytoplasmic enzymes.
Similar
analyses were conducted with a variety of catabolic and anabolic
cytoplasmic enzymes (Table 6). These
proteins showed similar homologue sizes, regardless of the domain or
kingdom analyzed. Averaging all of the statistically significant
results in Table 6 revealed that, on average, eucaryotic enzymes are
only 3% larger than the homologous bacterial enzymes and archaeal
enzymes are only 3% smaller than the homologous bacterial enzymes.
These average size differences are much less than for the integral
membrane transport proteins analyzed (Tables 1 and 4). Moreover, among the Eucarya kingdoms, animal and fungal homologues are
essentially the same size while plant homologues are only about 1%
smaller on average. This last mentioned average size difference is not statistically significant. Thus, cytoplasmic enzymes do not appear to
exhibit the appreciable size differences that were observed for
integral membrane proteins.
Statistical significance of the observed homologue size
differences.
To test for statistically significant differences in
transport protein lengths between phylogenetic groups, the data were analyzed using two-tailed Sign tests (17). In these
analyses, comparisons were made between paired domains of life, or
between paired kingdoms within the Eucarya domain, in terms
of average lengths of amino acyl sequences within the protein families
(Tables 1 to 5). The Sign test is a qualitative, nonparametric
paired-sample test that utilizes only the direction of difference (< or >) between paired data. As such, it requires no assumptions
regarding the distribution of data either within or between sample
groups. We felt that such assumptions might be unwarranted given the
size variation observed within the taxonomic groups with respect to average length of the proteins within the families represented. Thus,
there proved to be more variation between protein families within each
domain than there was between domains in any particular protein family.
Each pair of domains or kingdoms was therefore compared independently.
A P value of 
0.05 was considered significant. Tabulated
data and associated Sign test P values are presented in
Table 7.
The results of the statistical analyses strongly support the conclusion
that transport protein length differs significantly
between domains in
all pairwise comparisons.
Archaea have significantly
shorter
transport proteins than
Bacteria, and both
Archaea and
Bacteria have shorter transport
proteins than
Eucarya. Tests were
generally less significant
in pairwise comparisons of
Eucarya kingdoms. Plants have
shorter transport proteins than either animals
or fungi, but the
difference in protein length between animals
and fungi is not
significant. Corresponding analyses of the ABC
receptors, membrane
proteins, and cytoplasmic energizers argued
for statistical
significance, although the actual size differences
between the archaeal
and bacterial energizers proved to be
minimal.
Localization of regions in homologues of secondary transporters
responsible for size differences between Bacteria,
Archaea, and Eucarya.
Five families of
secondary carriers were analyzed in detail to determine what portions
of these proteins exhibit the greatest size variation. For this
purpose, five sequence-divergent members of each family from each of
the three domains of living organisms were selected for analysis. These
sequences were multiply aligned using the CLUSTAL X program
(13), and hydropathy analyses were conducted using the
TMpred program (2). The results of these analyses are
summarized in Table 8.
For each family, the bacterial homologues are presented
first, the archaeal homologues are presented second, and the eucaryotic
proteins are presented last. Table
8 presents (i) the organismal
domains, (ii) the protein abbreviations, (iii) the size of each
individual protein, (iv) the database and accession number, allowing
easy access to the sequence of that protein, (v) the number of
putative
TMSs predicted using the TMpred program, (vi) the size
of the
N-terminal hydrophilic domain (N) in number of amino acyl
residues,
(vii) the residues predicted to comprise the individual
TMSs (1 to 14),
and (viii) the size of the C-terminal hydrophilic
domain
(C).
The first family shown is the Ca
2+:cation antiporter (CaCA)
family (Table
8). The size differences between the proteins are
apparent when examining the data summarized in column 3. In column
5, it can be seen that there is substantial variation in the predicted
number of TMSs. For this family and other families examined, some
of
this variation may represent experimental error due to limitations
of
the TMPred program. For the CaCA family, there is little variation
in
the sizes of the N-terminal and C-terminal hydrophilic domains
(between
0 and 40 residues each). However, three of the eucaryotic
proteins (all
from animals) (CaSA2 Bta, Orfl Cel, and CaSA Dme)
show large inter-TMS
loops between TMSs 6 and 7. These loops are
between 455 and 566 amino
acyl residues long, accounting for most
of the size differences
observed for these proteins compared with
other homologues examined.
These loops are predicted to be of
29 to 38 residues for the bacterial
proteins, of 11 to 22 residues
for the archaeal proteins, and of 14 and
10 residues for the two
remaining eucaryotic proteins, plant and yeast
proteins, respectively.
Additionally, it can be seen that other
eucaryotic inter-TMS loops
are of somewhat increased size relative to
their procaryotic counterparts.
For example, loops 1 and 2 (between
TMSs 1 and 2) contain 1 to
22 residues in procaryotic proteins but 34 to 99 residues in the
eucaryotic homologues; loops 2 and 3 in the
procaryotic proteins
are 16 to 19 residues long while those in the
eucaryotic proteins
are 21 to 23 residues long; and loops 3 and 4 in
the procaryotic
proteins are of 7 to 18 residues while those in the
eucaryotic
proteins are of 15 to 23 residues. Finally, the program
predicts
11 TMSs for the bacterial homologues, 9 or 10 TMSs for the
archaeal
homologues, and either 10 or 12 TMSs for the eucaryotic
proteins.
All of these differences, when taken together, account for
the
observed size variations of the individual proteins of the CaCA
family.
The second family listed in Table
8 is the inorganic phosphate
transporter (Pit) family. All but one of the Pit family members
has a
small N-terminal hydrophilic region, the one exception being
the plant
Pit Ath homologue, which has an N-terminal hydrophilic
domain of 126 residues. The archaeal proteins generally have shorter
hydrophilic N
termini than the bacterial proteins. Further, the
hydrophilic C termini
of all homologues are short (1 to 26 residues).
The major size
variations observed between the procaryotic and
eucaryotic proteins of
this family are in loops 7-8 and 8-9. For
example, Orf Cel is
predicted to have a somewhat large loop 8-9
(46 residues), Glvr Hsa
and Nps Sce have a large loop 7-8 (62
and 206 residues, respectively),
and Pho4 Ncr has large loops
7-8 and 8-9 (122 and 89 residues,
respectively). Differences in
the number of putative TMSs predicted are
also observed, with
Orf Cel and Pho4 Ncr predicted to have more TMSs
than the other
homologues.
The monovalent cation:proton antiporter families (CPA1 and CPA2) show
similarly sized N-terminal hydrophilic domains, but
their C-terminal
hydrophilic domains differ substantially in size
(Table
8). Thus, in
the CPA1 family, four of the bacterial homologues
have hydrophilic
extensions of 21 to 32 residues, but one protein,
Orf Bsu, has a
hydrophilic extension of 131 residues. Similarly,
four of the archaeal
proteins have C-terminal hydrophilic extensions
of 7 to 25 residues,
but one protein (Nhe2 Afu) has an extension
of 124 residues. Finally,
all of the eucaryotic proteins have
long C-terminal hydrophilic domains
of 102 to 394 residues. In
the CPA2 family, the major size differences
are also in the C-terminal
regions. In this family, the bacterial
C-terminal extensions are
large (226 to 282 residues), while all but
one of the archaeal
extensions are short (6 to 21 residues except for
that in Orf
Mth, which is 174 residues in length). All of the
eucaryotic proteins
have large hydrophilic C termini (185 to 277 residues). The two
yeast proteins additionally exhibit large loops
between their
final two C-terminal TMSs (308 and 444 residues,
respectively).
Finally, several proteins of the divalent anion:Na
+
symporter family exhibit major size differences in their N-terminal
hydrophilic
domains (Table
8), although differences in loop sizes and
numbers
of putative TMSs contribute significantly to the overall
protein
size differences. Most of these proteins show small C-terminal
hydrophilic
extensions.
In summary, we have found that the positional basis for the size
variations observed between secondary carrier homologues
from the three
domains of life depends primarily on the family
and secondarily on the
individual proteins within that family.
Some families show differences
primarily in the N-terminal hydrophilic
domains, others show
differences in the C-terminal hydrophilic
domains, and still others
show differences in specific inter-TMS
loop regions. Most families
exhibit size differences between homologues
that represent a
combination of these effects, with one of these
effects
predominating.
| |
DISCUSSION |
The average size differences for the various types of protein
homologues analyzed are summarized in Table
9. When all family size differences are
averaged, integral membrane transport proteins of bacteria are 8%
larger than their archaeal homologues and 40% smaller than their
eucaryotic homologues. When the three constituents of
procaryotic-specific ABC-type uptake permeases were examined, the
archaeal extracytoplasmic receptors proved to be 7% larger than their
bacterial homologues, on average, while the membrane and cytoplasmic
constituents were 3 to 4% smaller. Homologous cytoplasmic enzymes
showed little or no significant difference between the three domains of
life (Table 9). Within the Eucarya kingdoms, integral
membrane transporters of plants proved to be significantly smaller than
those of animals (21%) and fungi (17%), although no corresponding
size differences were noted for homologous cytoplasmic enzymes. These
observations clearly show that during evolution, integral membrane
transport proteins have been subject to different pressures giving rise
to size differences that are not paralleled in cytoplasmic proteins or
extracytoplasmic receptors. In fact, the latter proteins exhibit
significant size differences between Bacteria and
Archaea that are opposite to those observed for the integral
membrane proteins. These observations must be explainable at the
molecular level.
The molecular explanation(s) for the protein size differences
documented in this report is currently elusive. Several investigators have noted that when plasmidic DNA sequences exhibiting short repetitive elements are transferred to yeast, the repeats tend to
increase in number, although the reverse is true in Escherichia coli (1, 5, 6, 12). The molecular basis for this
observation is not known, but if operative on chromosomal DNA over an
extended period of evolutionary time, it could account for the observed average membrane protein homologue size differences. However, because
the cytoplasmic proteins analyzed do not show this trend and because
extracytoplasmic receptors show the opposite trend, we disfavor such an explanation.
Other explanations may exist. Our domain analyses summarized in Table 8
show that the major size differences in secondary carrier proteins
occur primarily in the N- and C-terminal hydrophilic extensions and
specific inter-TMS loops of these integral membrane proteins, and that
the locations where the major size differences occur are family
specific. Sometimes the numbers of putative -helical TMSs differ,
but these differences may be in part artifactual and do not generally
account for the size variations observed. Hydrophilic domains in
transporters are known to play regulatory roles in various well-studied
procaryotic and eucaryotic transport proteins (3, 14). It
is possible that Eucarya have been under greater pressure to
evolve regulatory domains controlling transport than have
Bacteria and that Bacteria have in turn been
under greater pressure to evolve such regions than have the
Archaea. If this possibility does account for the observed
size differences, then plants must have been under less stringent
pressure to evolve protein regulatory sequences than were animals and
fungi. Moreover, cytoplasmic enzymes have not been subject to similar
constraints. These observations may have predictive value for purposes
of annotation. However, one can expect that multiple explanations will
account for the size variations observed.
It is clear that the studies reported here pose more questions than
they have answered. What are the membrane structural features or
mechanistic features that promote the observed size differences? Are
repeated DNA sequences present in the structural genes for these
proteins, and if so, do numbers of repeats contribute to or even
account for the size differences observed for their protein products?
What are the physiological benefits to organisms in the three domains
of life to promote homologue size variation? What accounts for the size
differences observed between plant transporters and those from other
Eucarya? Further computational experimentation, currently in
progress, will be required to provide answers to these interesting questions.
| |
ACKNOWLEDGMENTS |
We thank Donna Yun, Monica Mistry, Milda Simonaitis, and
Yolanda Anglin for their assistance in the preparation of this manuscript.
Work in the authors' laboratory was supported by NIH grant no. 2R01
AI14176 from the National Institute of Allergy and Infectious Diseases
and no. 9RO1 GM55434 from the National Institute of General Medical
Sciences, as well as by the M. H. Saier, Sr. Memorial Research Fund.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Biology, University of California at San Diego, La Jolla, CA
92093-0116. Phone: (858) 534-4084. Fax: (858) 534-7108. E-mail:
msaier{at}ucsd.edu.
Permanent address: Department of Life Science, Jeonju University,
Chonju, Korea.
| |
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Journal of Bacteriology, February 2001, p. 1012-1021, Vol. 183, No. 3
0021-9193/01/$04.00+0 DOI: 10.1128/JB.183.3.1012-1021.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Top
Abstract
Introduction
