1 Program in Biological Sciences, University of California, San Francisco, CA
94143-0444, USA
2 Department of Physiology, University of California, San Francisco, CA
94143-0444, USA
3 Department of Medicine, University of California, San Francisco, CA
94143-0444, USA
* Author for correspondence (e-mail: vrl{at}itsa.ucsf.edu )
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Summary |
---|
Key words: Translocon, Endoplasmic reticulum, Biogenesis, Signal transduction, Topogenesis
![]() |
Introduction |
---|
Here we focus on the biosynthesis of mammalian integral membrane proteins
that use one or more -helical membrane-spanning domains to integrate
into the lipid bilayer. Some integral membrane proteins have a single
membrane-spanning domain (bitopic), others have several (polytopic). Bitopic
membrane proteins are categorized according to the properties of their
transmembrane (TM) domains (Fig.
1). During biogenesis, the N-terminus of a type I integral
membrane protein is in the ER lumen, whereas in a type II integral membrane
protein the N-terminus is in the cytoplasm. Integral membrane proteins that
use their first transmembrane domain as both a signal sequence and a stop
transfer sequence are classified as signal-anchored proteins. C-terminally
anchored proteins have a signal-anchored domain at the extreme C-terminus.
|
![]() |
Overview of integral membrane protein biogenesis |
---|
Synthesis of polytopic membrane proteins is more complex than that of
bitopic membrane proteins. For example, instead of synthesizing the cytosolic
domain of a type I membrane protein and then terminating translocation, the
translocation machinery has to be switched on again and begin to translocate
another TM domain, another lumenal domain, etc. How are these switches
controlled? They are regulated by several factors that can act independently
or in concert. The hydrophobicity of the TM domain plays an important role.
However, some proteins also have a stop transfer effector (STE) sequence, a
domain flanking the hydrophobic membrane-spanning domain, which appears to
instruct the translocon not to translocate the domain intended for the cytosol
(Yost et al., 1990). In
addition, some TM domains facilitate the integration of other TM domains into
the same protein.
![]() |
Co-translational membrane protein biosynthesis |
---|
|
Similar to signal sequences, TM domains have differing requirements for
TRAM during integration. Attempts to determine exactly how a TM domain passes
from the translocon into the lipid bilayer have produced seemingly conflicting
results. First it was reported that the TM domain of a type I membrane protein
remains associated with translocon components until translation termination
(Thrift et al., 1991). The TM
domain transits from an environment in which it contacts Sec61
to an
environment in which it contacts TRAM; this suggests lateral movement and
lipid integration (Do et al.,
1996
). More recent studies of a signal-anchored protein led to the
alternative model that integration of the TM domain into the lipid bilayer
occurs shortly after synthesis and is not dependent on TRAM or translation
termination (Mothes et al.,
1997
). Changing the properties of the TM domain decreases its
ability to partition into the lipid bilayer cotranslationally and enables the
nascent chain to crosslink to TRAM
(Heinrich et al., 2000
). It is
highly likely that both models are correct and that only some TM domains
interact with TRAM during integration, probably those that linger in the
translocon.
The translocon must be dynamic. Unlike many other pores, substrates can
move through it in two dimensions: into the ER lumen or into the ER membrane.
To accommodate the needs of different substrates; it must also be capable of
expanding. Fluorescence quenching experiments in the absence of a ribosome
indicate that the pore has a diameter of between 9 and 15 Å
(Hamman et al., 1997);
however, recent electron microscopy data suggest that the pore is closed but
dimpled (Beckmann et al.,
2001
). Sec61 complexes visualized by electron microscopy had a
pore size of
20Å, which is large enough for a single
helix
(Hanein et al., 1996
). Other
experimental evidence, both direct and indirect, indicates that the channel
has a diameter of 40-60Å, which could accommodate up to six TM domains
(Borel and Simon, 1996
;
Hamman et al., 1997
).
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A role for intraprotein interactions |
---|
Intraprotein interactions that affect membrane protein biosynthesis can be
classified as weak integrators or strong orientation effectors. TM domains
that require interaction with adjacent TM domains for proper integration (weak
integrators) are present in the multidrug resistance protein MDR1, the
Neurospora proton transporter H+-ATPase and the
erythrocyte protein band 3 (Skach and
Lingappa, 1993; Lin and
Addison, 1995
; Ota et al.,
2000
). In these proteins, specific TM domains can target and
properly orient independently, but integration efficiency is poor if the TM
domain is unable to interact with adjacent TM domains. Increasing the distance
between TM domains reduces the cis interactions and results in translocation
of the weak TM domain (Fig.
3a). Orientation of TM domains can also be affected by cis
interactions. In the case of the erythrocyte protein band 3, the eighth TM
domain (TM8) a strong orientation effector is required for
both proper orientation and integration of TM7
(Fig. 3b). TM8 is such a strong
orientation effector that it can cause the integration of both hydrophobic and
hydrophilic domains (Ota et al.,
1998b
).
|
![]() |
The role of other protein factors |
---|
Interprotein interactions can play a role in both TM domain integration and
STE recognition. PrP can be synthesized in three different topological forms:
NtmPrP, a type I membrane protein in which the N-terminus is in the
lumen; CtmPrP, a type II membrane protein in which the C-terminus
is in the lumen; and a secretory form called secPrP. In vitro, in
the absence of translocation accessory factor (TrAF) activity, PrP is made
exclusively as the CtmPrP form
(Hegde et al., 1998b), which
causes neurodegeneration in mice and humans when synthesized in vivo
(Hegde et al., 1998a
). Little
more is known about TrAF, but perhaps it regulates how or when other factors,
such as TRAM, interact with PrP and probably with many other proteins. Early
studies suggested that receptor-mediated recognition events occur during
translocation starting and stopping (Mize
et al., 1986
), which is consistent with the subsequent
identification of STEs (Yost et al.,
1990
). Recently, crosslinking studies of an IgM STE sequence
identified two membrane proteins involved in STE recognition or function
(Falcone et al., 1999
).
Characterization of these STE receptors will be one of the next steps toward
understanding how integration is regulated.
Chaperone activity also appears to have a role in integration. At least one
protein factor in the ER membrane is proposed to be responsible for proper
biosynthesis of the gap junction component connexin. In vitro synthesis or in
vivo overexpression of connexin results in the production of aberrantly
cleaved molecules because signal peptidase mistakes the first TM domain for a
signal peptide. In vivo cleavage of the TM domain is believed to be prevented
by an unidentified chaperone in the membrane, which recognizes the nascent
chain and blocks the access of signal peptidase. In vitro this chaperone may
be absent or non-functional (Falk and
Gilula, 1998).
Co-translocational modification of nascent chains can also affect
biosynthesis. Oligosaccharyl transferase (OST) associates with the translocon
and glycosylates nascent chains as they emerge in the ER. To look at possible
effects of glycosylation on TM domain orientation, Goder et al.
(Goder et al., 1999) created a
chimeric protein that can be synthesized in either of two topological forms.
When they engineered glycosylation sites, they found that reorientation of a
transmembrane domain in the translocon was prevented by glycosylation of the
lumenal TM loop. These results suggest that regulation of glycosylation of
native proteins can control folding and orientation of proteins according to
the needs of the cell.
The interprotein interactions described above probably affect biosynthesis
of many different membrane proteins. Substrate-specific interprotein
interactions also affect biosynthesis. In the membrane, as in the cytosol,
proteins associate to form functional complexes. Studies of the P-type
Na+/K+-ATPase revealed that the correct insertion of the
polytopic subunit seventh and eighth TM domains requires association
of the bitopic ß subunit with the extra-cytosolic loop between the two TM
domains (Beguin et al., 1998
).
When the ß subunit encounters the proper region of the
subunit,
it appears to induce a conformational change that promotes proper folding and
integration of the TM domains. Specific trans interactions that facilitate
proper formation of membrane protein complexes might prevent the nascent chain
from making undesirable or deleterious associations with itself or other
proteins.
We are beginning to understand more about the proteins that influence membrane protein biosynthesis, but there is much left to learn. Characterization of both TrAFs and the STE receptors will improve our understanding of the mechanism of membrane domain integration, as will additional examples of substrate-specific interactions. Identification of the chaperone involved in connexin biosynthesis will enable us to learn how membrane chaperones function. Finally, discovery of proteins that use glycosylation to control orientation in vivo will clarify other ways in which biosynthesis can be regulated.
![]() |
A role for signal sequences in orientation and integration |
---|
![]() |
Post-translational targeting and integration |
---|
![]() |
Predictive algorithms for integral membrane protein topology |
---|
|
Integral membrane proteins have several common features. First, the
membrane-spanning domain is generally a hydrophobic helix.
Interestingly, several residues considered to be helix breakers in aqueous
environments, such as glycine, isoleucine and valine, do not disrupt helix
formation in the lipid environment of the membrane
(Deber et al., 2001
). Another
trend is the `positive-inside' rule: the cytoplasmic portion of the integral
membrane protein tends to be enriched in positively charged residues
(von Heijne, 1992
). The
problem for topology prediction is that these `rules' are far from absolute.
For example, the positive-inside rule, although largely true in prokaryotes,
for which it was formulated, appears to be less true in eukaryotes
(Andrews et al., 1992
).
Many prediction algorithms have been developed during the past twenty
years. The first prediction methods simply evaluated the hydrophobicity of
individual residues; regions with several hydrophobic residues were predicted
to be TM domains (Kyte and Doolittle,
1982). The dense alignment surface (DAS) method analyzes the
frequency with which groups of amino acids are found in the TM domains of
proteins in the test set (Cserzo et al.,
1997
). The latest generation of topology-prediction programs use
machine-learning algorithms called hidden Markov models (HMM), which are
trained by analyzing the residues that tend to occupy defined regions in the
integral membrane proteins. Two such algorithms, transmembrane HMM (TMHMM) and
HMMTOP, assess five or seven (respectively) defined regions of an integral
membrane protein, such as the helix core, the TM domain boundaries and
cytosolic and lumenal domains. Instead of looking at the probability of
individual or groups of amino acids to populate each region as in TMHMM,
HMMTOP assigns topology by comparing the residues found in one region with
those found in other regions (Sonnhammer
et al., 1998
; Tusnady and
Simon, 1998
). To evaluate a protein, the programs look for
distribution of amino acids in patterns similar to those defined in the
training set.
Integral membrane protein topology prediction programs generally attempt to provide four different kinds of information: (1) whether or not the protein is likely to be an integral membrane protein; (2) how many membrane-spanning domains the protein has; (3) the orientations of the transmembrane domains; and (4) the boundaries of the membrane and non-membrane domains. Incorrect predictions can come from several different sources. The hydrophobic core of a soluble protein can be misidentified as a TM domain. Short TM domains or TM domains containing charged residues can be overlooked, as can regions adjacent to strong orientation effector sequences. In Fig. 4 the number of TM domains predicted for band 3 by each program is variable, and even the program that predicts the correct number of TM domains fails to identify the location of the first TM domain correctly. The transmembrane hidden Markov model (TMHMM) predicts an odd number of transmembrane domains and consequent localization of the band 3 C-terminus to the lumen. Prediction errors in the topology assignment of an early TM domain in a multi-spanning membrane protein can result in an incorrectly predicted orientation of the subsequent TM domains.
The training set used by a program can limit its predictive power. Current
test sets contain limited information about eukaryotic membrane proteins,
because the topologies of relatively few eukaryotic integral membrane proteins
have been experimentally determined. Much of the information we do have has
come from biochemical analysis. Relatively few crystal structures are
available, because membrane proteins are generally hard to crystallize. Bias
in the training set comes from both the small sample size available and the
fact that certain membrane proteins are more amenable to structural analysis
(Rosenbusch et al., 2001). It
is very difficult to determine the exact boundaries of a TM domain by
biochemical and structural approaches and so the accuracy of boundaries
assigned by prediction programs are difficult to assess
(Deber et al., 2001
).
Prediction algorithms will continue to develop and take advantage of new technology. Significant improvement, however, will probably require a better understanding of integral membrane protein biosynthesis. As the properties that mediate cis and trans protein interactions are defined, they can be included in the algorithms, perhaps identifying those proteins whose topologies are most difficult to predict.
![]() |
Conclusions |
---|
The new information about cis interactions during biosynthesis should
affect how we think about membrane protein folding. The current model of
membrane folding involves two stages: (1) folding of independent TM domains;
and (2) assembly of those separate domains into a functional protein through
lateral helix-helix interactions (Popot
and Engelman, 1990; Popot and
Engelman, 2000
). This model may not fully consider the
relationship between folding, orientation, integration and assembly. New data
suggest that some TM domains may never exist as independent TM domains. In
some cases (such as the P-type Na+/K+-ATPase described
above), multiprotein complex formation is linked to TM domain recognition,
orientation and integration. During membrane protein folding, generation of a
final folded state is not the result of a linear progression from primary to
quaternary structure. Instead, secondary and tertiary structure can be formed
simultaneously.
A growing body of evidence that many factors regulate the recognition, orientation and integration of TM domains indicates a level of complexity, and perhaps topological heterogeneity, not apparent from the amino-acid sequence alone. The molecular bases of the cis and trans interactions that affect integral membrane protein biogenesis are not yet well enough understood for us to assess whether they can be incorporated into prediction algorithms. Until such time, although prediction programs have improved significantly, they should still be used cautiously.
Regulation at the levels of transcription, splicing and translation is universally acknowledged, but regulation also occurs during translocation, integration and perhaps even folding. It is highly probable that the decision to make a specific form of a multi-topogenic protein occurs during biogenesis, prior to integration. Cell signaling cascades can regulate integral membrane protein biosynthesis by utilizing chaperones and other accessory factors. Controlling the translocon environment affects cis and trans interactions. Understanding the intricate regulation of integral membrane protein biosynthesis will enable researchers in many fields to understand how these proteins function.
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Acknowledgments |
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References |
---|
Andrews, D. W., Young, J. C., Mirels, L. F. and Czarnota, G.
J. (1992). The role of the N region in signal sequence and
signal-anchor function. J. Biol. Chem.
267,7761
-7769.
Beckmann, R., Spahn, C. M. T., Eswar, N., Helmers, J., Penczek, P. A., Sali, A., Frank, J. and Blobel, G. (2001). Architecture of the protein-conducting channel associated with the translating 80S ribosome. Cell 107,361 -372.[Medline]
Beguin, P., Hasler, U., Beggah, A., Horisberger, J. D. and
Geering, K. (1998). Membrane integration of Na,K-ATPase
alpha-subunits and beta-subunit assembly. J. Biol.
Chem. 273,24921
-24931.
Booth, P. J. and Curran, A. R. (1999). Membrane protein folding. Curr. Opin. Struct. Biol. 9, 115-121.[Medline]
Borel, A. C. and Simon, S. M. (1996). Biogenesis of polytopic membrane proteins membrane segments assemble within translocation channels prior to membrane integration. Cell 85,379 -389.[Medline]
Corsi, A. K. and Schekman, R. (1996). Mechanism
of polypeptide translocation into the endoplasmic reticulum. J.
Biol. Chem. 271,30299
-30302.
Cserzo, M., Wallin, E., Simon, I., vonHeijne, G. and Elofsson, A. (1997). Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: the dense alignment surface method. Protein Eng. 10,673 -676.[Abstract]
Deber, C. M., Wang, C., Liu, L. P., Prior, A. S., Agrawal, S.,
Muskat, B. L. and Cuticchia, A. J. (2001). TM Finder: A
prediction program for transmembrane protein segments using a combination of
hydrophobicity and nonpolar phase helicity scales. Protein
Sci. 10,212
-219.
Do, H., Falcone, D., Lin, J., Andrews, D. W. and Johnson, A. E. (1996). The cotranslational integration of membrane proteins into the phospholipid bilayer is a multistep process. Cell 85,369 -378.[Medline]
Dunlop, J., Jones, P. C. and Finbow, M. E. (1995). Membrane insertion and assembly of Ductin a polytopic channel with dual orientations. EMBO J. 14,3609 -3616.[Abstract]
Evans, E. A., Gilmore, R. and Blobel, G. (1986). Purification of microsomal signal peptidase as a complex. Proc. Natl. Acad. Sci. USA 83,581 -585.[Abstract]
Falcone, D., Do, H., Johnson, A. E. and Andrews, D. W.
(1999). Negatively charged residues in the IgM stop-transfer
effector sequence regulate transmembrane polypeptide integration.
J. Biol. Chem. 274,33661
-33670.
Falk, M. M. and Gilula, N. B. (1998). Connexin
membrane protein biosynthesis is influenced by polypeptide positioning within
the translocon and signal peptidase access. J. Biol.
Chem. 273,7856
-7864.
Fulga, T. A., Sinning, I., Dobberstein, B. and Pool, M. R.
(2001). SR beta coordinates signal sequence release from SRP with
ribosome binding to the translocon. EMBO J.
20,2338
-2347.
Goder, V., Bieri, C. and Spiess, M. (1999).
Glycosylation can influence topogenesis of membrane proteins and reveals
dynamic reorientation of nascent polypeptides within the translocon.
J. Cell Biol. 147,257
-265.
Gorlich, D., Hartmann, E., Prehn, S. and Rapoport, T. A. (1992). A protein of the endoplasmic reticulum involved early in polypeptide translocation. Nature 357, 47-52.[Medline]
Gorlich, D. and Rapoport, T. A. (1993). Protein translocation into proteoliposomes reconstituted from purified components of the endoplasmic reticulum membrane. Cell 75,615 -630.[Medline]
Haigh, N. and Johnson, A. (2002). A new role
for BiP: closing the aqueous translocon pore during protein integration into
the ER membrane. J. Cell Biol.
156,261
-270.
Hamman, B. D., Chen, J. C., Johnson, E. E. and Johnson, A. E. (1997). The aqueous pore through the translocon has a diameter of 40-60 A during cotranslational protein translocation at the ER membrane. Cell 89,535 -544.[Medline]
Hamman, B. D., Hendershot, L. M. and Johnson, A. E. (1998). BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation. Cell 92,747 -758.[Medline]
Hanein, D., Matlack, K. E., Jungnickel, B., Plath, K., Kalies, K. U., Miller, K. R., Rapoport, T. A. and Akey, C. W. (1996). Oligomeric rings of the Sec61p complex induced by ligands required for protein translocation. Cell 87,721 -732.[Medline]
Hegde, R. S. and Lingappa, V. R. (1999). Regulation of protein biogenesis at the endoplasmic reticulum membrane. Trends Cell Biol. 9,132 -137.[Medline]
Hegde, R. S., Mastrianni, J. A., Scott, M. R., DeFea, K. A.,
Tremblay, P., Torchia, M., DeArmond, S. J., Prusiner, S. B. and Lingappa, V.
R. (1998a). A transmembrane form of the prion protein in
neurodegenerative disease. Science
279,827
-834.
Hegde, R. S., Voigt, S. and Lingappa, V. R. (1998b). Regulation of protein topology by trans-acting factors at the endoplasmic reticulum. Mol. Cell 2, 85-91.[Medline]
Hegde, R. S., Voigt, S., Rapoport, T. A. and Lingappa, V. R. (1998c). TRAM regulates the exposure of nascent secretory proteins to the cytosol during translocation into the endoplasmic reticulum. Cell 92,621 -631.[Medline]
Heinrich, S. U., Mothes, W., Brunner, J. and Rapoport, T. A. (2000). The Sec61p complex mediates the integration of a membrane protein by allowing lipid partitioning of the transmembrane domain. Cell 102,233 -244.[Medline]
Kelleher, D. J., Kreibich, G. and Gilmore, R. (1992). Oligosaccharyltransferase activity is associated with a protein complex composed of ribophorins I and II and a 48 kd protein. Cell 69,55 -65.[Medline]
Kim, P. K., JaniakSpens, F., Trimble, W. S., Leber, B. and Andrews, D. W. (1997). Evidence for multiple mechanisms for membrane binding and integration via carboxyl-terminal insertion sequences. Biochemistry 36,8873 -8882.[Medline]
Kim, P. K., Hollerbach, C., Trimble, W. S., Leber, B. and
Andrews, D. W. (1999). Identification of the endoplasmic
reticulum targeting signal in vesicle-associated membrane proteins.
J. Biol. Chem. 274,36876
-36882.
Kim, S. J., Rahbar, R. and Hegde, R. S. (2001).
Combinatorial control of prion protein biogenesis by the signal sequence and
transmembrane domain. J. Biol. Chem.
276,26132
-26140.
Kutay, U., Ahnert-Hilger, G., Hartmann, E., Wiedenmann, B. and Rapoport, T. A. (1995). Transport route for synaptobrevin via a novel pathway of insertion into the endoplasmic reticulum membrane. EMBO J. 14,217 -223.[Abstract]
Kyte, J. and Doolittle, R. F. (1982). A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157,105 -132.[Medline]
Lin, J. L. and Addison, R. (1995). A novel
integration signal that is composed of two transmembrane segments is required
to integrate the Neurospora plasma membrane H+-Atpase into
microsomes. J. Biol. Chem.
270,6935
-6941.
Lopez, C. D., Yost, C. S., Prusiner, S. B., Myers, R. M. and Lingappa, V. R. (1990). Unusual topogenic sequence directs prion protein biogenesis. Science 248,226 -229.[Medline]
Matlack, K. E., Mothes, W. and Rapoport, T. A. (1998). Protein translocation: tunnel vision. Cell 92,381 -390.[Medline]
Mize, N. K., Andrews, D. W. and Lingappa, V. R. (1986). A stop transfer sequence recognizes receptors for nascent chain translocation across the endoplasmic reticulum membrane. Cell 47,711 -719.[Medline]
Mothes, W., Heinrich, S. U., Graf, R., Nilsson, I., von Heijne, G., Brunner, J. and Rapoport, T. A. (1997). Molecular mechanism of membrane protein integration into the endoplasmic reticulum. Cell 89,523 -533.[Medline]
Ota, K., Sakaguchi, M., Hamasaki, N. and Mihara, K.
(1998a). Assessment of topogenic functions of anticipated
transmembrane segments of human band 3. J. Biol. Chem.
273,28286
-28291.
Ota, K., Sakaguchi, M., von Heijne, G., Hamasaki, N. and Mihara, K. (1998b). Forced transmembrane orientation of hydrophilic polypeptide segments in multispanning membrane proteins. Mol. Cell 2,495 -503.[Medline]
Ota, K., Sakaguchi, M., Hamasaki, N. and Mihara, K.
(2000). Membrane integration of the second transmembrane segment
of band 3 requires a closely apposed preceding signal-anchor sequence.
J. Biol. Chem. 275,29743
-29748.
Palade, G. (1975). Intracellular aspects of the process of protein synthesis. Science 189,347 -358.[Medline]
Popot, J. L. and Engelman, D. M. (1990). Membrane protein folding and oligomerization the 2-stage model. Biochemistry 29,4031 -4037.[Medline]
Popot, J. L. and Engelman, D. M. (2000). Helical membrane protein folding, stability, and evolution. Annu. Review Biochem. 69,881 -922.[Medline]
Popov, M., Tam, L. Y., Li, J. and Reithmeier, R. A.
(1997). Mapping the ends of transmembrane segments in a polytopic
membrane protein. Scanning N-glycosylation mutagenesis of extracytosolic loops
in the anion exchanger, band 3. J. Biol. Chem.
272,18325
-18332.
Rosenbusch, J. P., Lustig, A., Grabo, M., Zulauf, M. and Regenass, M. (2001). Approaches to determining membrane protein structures to high resolution: do selections of subpopulations occur? Micron 32,75 -90.[Medline]
Rothman, R. E., Andrews, D. W., Calayag, M. C. and Lingappa, V.
R. (1988). Construction of defined polytopic integral
transmembrane proteins. The role of signal and stop transfer sequence
permutations. J. Biol. Chem.
263,10470
-10480.
Rutkowski, D. T., Lingappa, V. R. and Hegde, R. S.
(2001). Substrate-specific regulation of the ribosome-translocon
junction by N-terminal signal sequences. Proc. Natl Acad. Sci.
USA 98,7823
-7828.
Sanders, C. R. and Nagy, J. K. (2000). Misfolding of membrane proteins in health and disease: the lady or the tiger? Curr. Opin. Struct. Biol. 10,438 -442.[Medline]
Skach, W. R. and Lingappa, V. R. (1993).
Amino-terminal assembly of human P-glycoprotein at the endoplasmic reticulum
is directed by cooperative actions of two internal sequences. J.
Biol. Chem. 268,23552
-23561.
Sonnhammer, E. L. L., von Heijne, G. and Krogh, A. (1998). A hidden Markov model for predicting transmembrane helices in protein sequences. Proc. Int. Conf. Intell. Syst. Mol. Biol. 6,175 -182.[Medline]
Tanner, M. J. (1997). The structure and function of band 3 (AE1): recent developments. Mol. Membr. Biol. 14,155 -165.[Medline]
Thrift, R. N., Andrews, D. W., Walter, P. and Johnson, A. E. (1991). A nascent membrane protein is located adjacent to ER membrane proteins throughout its integration and translation. J. Cell Biol. 112,809 -821.[Abstract]
Tusnady, G. E. and Simon, I. (1998). Principles governing amino acid composition of integral membrane proteins: Application to topology prediction. J. Mol. Biol. 283,489 -506.[Medline]
Tusnady, G. E. and Simon, I. (2001). The HMMTOP
transmembrane topology prediction server.
Bioinformatics 17,849
-850.
Voigt, S., Jungnickel, B., Hartmann, E. and Rapoport, T. A. (1996). Signal sequence-dependent function of the TRAM protein during early phases of protein transport across the endoplasmic reticulum membrane. J. Cell Biol. 134, 25-35.[Abstract]
von Heijne, G. (1992). Membrane protein structure prediction Hydrophobicity analysis and the positive-inside rule. J. Mol. Biol. 225,487 -494.[Medline]
von Heijne, G. (1999). Recent advances in the understanding of membrane protein assembly and structure. Q. Rev. Biophys. 32,285 -307.[Medline]
Wahle, S. and Stoffel, W. (1998). Cotranslational integration of myelin proteolipid protein (PLP) into the membrane of endoplasmic reticulum: Analysis of topology by glycosylation scanning and protease domain protection assay. Glia 24,226 -235.[Medline]
Walter, P. and Johnson, A. E. (1994). Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Annu. Rev. Cell Biol. 10, 87-119.
Yost, C. S., Lopez, C. D., Prusiner, S. B., Myers, R. M. and Lingappa, V. R. (1990). Non-hydrophobic extracytoplasmic determinant of stop transfer in the prion protein. Nature 343,669 -672.[Medline]
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