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Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane.

Zhang L, Polyansky A, Buck M - PLoS ONE (2015)

Bottom Line: Plexin-B2 does not form stable dimers due to the presence of TM prolines.The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane.The structures suggest experimental tests and will be useful for the interpretation of future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.

ABSTRACT
Single-pass transmembrane (TM) receptors transmit signals across lipid bilayers by helix association or by configurational changes within preformed dimers. The structure determination for such TM regions is challenging and has mostly been accomplished by NMR spectroscopy. Recently, the computational prediction of TM dimer structures is becoming recognized for providing models, including alternate conformational states, which are important for receptor regulation. Here we pursued a strategy to predict helix oligomers that is based on packing considerations (using the PREDDIMER webserver) and is followed by a refinement of structures, utilizing microsecond all-atom molecular dynamics simulations. We applied this method to plexin TM receptors, a family of 9 human proteins, involved in the regulation of cell guidance and motility. The predicted models show that, overall, the preferences identified by PREDDIMER are preserved in the unrestrained simulations and that TM structures are likely to be diverse across the plexin family. Plexin-B1 and -B3 TM helices are regular and tend to associate, whereas plexin-A1, -A2, -A3, -A4, -C1 and -D1 contain sequence elements, such as poly-Glycine or aromatic residues that distort helix conformation and association. Plexin-B2 does not form stable dimers due to the presence of TM prolines. No experimental structural information on the TM region is available for these proteins, except for plexin-C1 dimeric and plexin-B1 - trimeric structures inferred from X-ray crystal structures of the intracellular regions. Plexin-B1 TM trimers utilize Ser and Thr sidechains for interhelical contacts. We also modeled the juxta-membrane (JM) region of plexin-C1 and plexin-B1 and show that it synergizes with the TM structures. The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane. The structures suggest experimental tests and will be useful for the interpretation of future studies.

No MeSH data available.


Model structures and dynamics of plexin-B1 TM-JM 9trimers.a) Two TM-JM trimer models for plexin-B1; structures are shown before MD refinement. Final structures are shown in Fig. B in S1 File. Left: extended clock-anticlock; Right: helix connected anticlock-anticlock. Distances of the JM C-terminal region from the membrane are plotted in Fig. F in S1 File. b) RMSF and c) <S2> for these plexin-B1 TM-JM trimers plotted as a function of sequence for the same simulations.
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pone.0121513.g007: Model structures and dynamics of plexin-B1 TM-JM 9trimers.a) Two TM-JM trimer models for plexin-B1; structures are shown before MD refinement. Final structures are shown in Fig. B in S1 File. Left: extended clock-anticlock; Right: helix connected anticlock-anticlock. Distances of the JM C-terminal region from the membrane are plotted in Fig. F in S1 File. b) RMSF and c) <S2> for these plexin-B1 TM-JM trimers plotted as a function of sequence for the same simulations.

Mentions: The juxta-membrane (JM) region, which connects the TM and intracellular domains was predicted to form a trimeric coiled coil. JM region was not visible in the X-ray structure of the trimer, but inferred from it [22]. Most of this region was, however seen in the X-ray structure of the plexin-B1 monomer [13]. Using the latter as a starting structure we built an anti-clockwise coiled-coil JM trimer as described in the Methods section and equilibrated it for 1.0 μs on Anton. The MD equilibrated clockwise or anti-clockwise TM trimer structures (described above) were then linked to this JM structure in several different ways: 1) as an extended connection in case of the TM clockwise/JM anti-clockwise arrangement, which was then restrained to become helical, 2) a bulged out-but otherwise irregular- connection for the TM anti-clock/JM anti-clock structure and finally, 3) the same with connections via helical (bent) structures, resulting in a total of 3 models. After equilibrating these configurations for 20 ns, it was clear that the structure started from model 2) showed very significant deviations from a helical structure and no further simulations were attempted. The structures started from model 1) and 3) were continued for 1.0 μs on Anton and had equilibrated. The initial and final structures are shown, partially in Fig. 6 and fully in Fig. 7a.


Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane.

Zhang L, Polyansky A, Buck M - PLoS ONE (2015)

Model structures and dynamics of plexin-B1 TM-JM 9trimers.a) Two TM-JM trimer models for plexin-B1; structures are shown before MD refinement. Final structures are shown in Fig. B in S1 File. Left: extended clock-anticlock; Right: helix connected anticlock-anticlock. Distances of the JM C-terminal region from the membrane are plotted in Fig. F in S1 File. b) RMSF and c) <S2> for these plexin-B1 TM-JM trimers plotted as a function of sequence for the same simulations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383379&req=5

pone.0121513.g007: Model structures and dynamics of plexin-B1 TM-JM 9trimers.a) Two TM-JM trimer models for plexin-B1; structures are shown before MD refinement. Final structures are shown in Fig. B in S1 File. Left: extended clock-anticlock; Right: helix connected anticlock-anticlock. Distances of the JM C-terminal region from the membrane are plotted in Fig. F in S1 File. b) RMSF and c) <S2> for these plexin-B1 TM-JM trimers plotted as a function of sequence for the same simulations.
Mentions: The juxta-membrane (JM) region, which connects the TM and intracellular domains was predicted to form a trimeric coiled coil. JM region was not visible in the X-ray structure of the trimer, but inferred from it [22]. Most of this region was, however seen in the X-ray structure of the plexin-B1 monomer [13]. Using the latter as a starting structure we built an anti-clockwise coiled-coil JM trimer as described in the Methods section and equilibrated it for 1.0 μs on Anton. The MD equilibrated clockwise or anti-clockwise TM trimer structures (described above) were then linked to this JM structure in several different ways: 1) as an extended connection in case of the TM clockwise/JM anti-clockwise arrangement, which was then restrained to become helical, 2) a bulged out-but otherwise irregular- connection for the TM anti-clock/JM anti-clock structure and finally, 3) the same with connections via helical (bent) structures, resulting in a total of 3 models. After equilibrating these configurations for 20 ns, it was clear that the structure started from model 2) showed very significant deviations from a helical structure and no further simulations were attempted. The structures started from model 1) and 3) were continued for 1.0 μs on Anton and had equilibrated. The initial and final structures are shown, partially in Fig. 6 and fully in Fig. 7a.

Bottom Line: Plexin-B2 does not form stable dimers due to the presence of TM prolines.The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane.The structures suggest experimental tests and will be useful for the interpretation of future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States of America.

ABSTRACT
Single-pass transmembrane (TM) receptors transmit signals across lipid bilayers by helix association or by configurational changes within preformed dimers. The structure determination for such TM regions is challenging and has mostly been accomplished by NMR spectroscopy. Recently, the computational prediction of TM dimer structures is becoming recognized for providing models, including alternate conformational states, which are important for receptor regulation. Here we pursued a strategy to predict helix oligomers that is based on packing considerations (using the PREDDIMER webserver) and is followed by a refinement of structures, utilizing microsecond all-atom molecular dynamics simulations. We applied this method to plexin TM receptors, a family of 9 human proteins, involved in the regulation of cell guidance and motility. The predicted models show that, overall, the preferences identified by PREDDIMER are preserved in the unrestrained simulations and that TM structures are likely to be diverse across the plexin family. Plexin-B1 and -B3 TM helices are regular and tend to associate, whereas plexin-A1, -A2, -A3, -A4, -C1 and -D1 contain sequence elements, such as poly-Glycine or aromatic residues that distort helix conformation and association. Plexin-B2 does not form stable dimers due to the presence of TM prolines. No experimental structural information on the TM region is available for these proteins, except for plexin-C1 dimeric and plexin-B1 - trimeric structures inferred from X-ray crystal structures of the intracellular regions. Plexin-B1 TM trimers utilize Ser and Thr sidechains for interhelical contacts. We also modeled the juxta-membrane (JM) region of plexin-C1 and plexin-B1 and show that it synergizes with the TM structures. The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane. The structures suggest experimental tests and will be useful for the interpretation of future studies.

No MeSH data available.