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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-C1 TM-JM dimers.a). Two models (c1.2, left and c1.1, right) for the plexin-C1 TM-JM dimer connected by helical segments before 1 μs of MD. b) RMSF and c) <S2> both plotted as a function of sequence. Data for helix A in black, helix B in red. Also see S1 and S2 Movies.
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pone.0121513.g008: Model structures and dynamics of plexin-C1 TM-JM dimers.a). Two models (c1.2, left and c1.1, right) for the plexin-C1 TM-JM dimer connected by helical segments before 1 μs of MD. b) RMSF and c) <S2> both plotted as a function of sequence. Data for helix A in black, helix B in red. Also see S1 and S2 Movies.

Mentions: In case of the plexin-C1 dimer [21], the crystal structure shows a coiled coil-like JM dimer (see Fig. G in S1 File for discussion and further analysis). The resolved part of the JM region needs to be extended to the membrane. It was modeled here, starting with the MD refined N- and C-terminally extended TM models, c1.1 and c1.2, which were then linked to the JM coiled-coil-like X-ray structure. The TM-JM junction was modeled in order to connect the TM and JM structures with continuing helices. However, we observed constraints during the modeling were imposed by the crossing angle of the TM region. These influence the packing of the junction, which is initially imperfect in one of the two helices in both structures (Fig. 8a).


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-C1 TM-JM dimers.a). Two models (c1.2, left and c1.1, right) for the plexin-C1 TM-JM dimer connected by helical segments before 1 μs of MD. b) RMSF and c) <S2> both plotted as a function of sequence. Data for helix A in black, helix B in red. Also see S1 and S2 Movies.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121513.g008: Model structures and dynamics of plexin-C1 TM-JM dimers.a). Two models (c1.2, left and c1.1, right) for the plexin-C1 TM-JM dimer connected by helical segments before 1 μs of MD. b) RMSF and c) <S2> both plotted as a function of sequence. Data for helix A in black, helix B in red. Also see S1 and S2 Movies.
Mentions: In case of the plexin-C1 dimer [21], the crystal structure shows a coiled coil-like JM dimer (see Fig. G in S1 File for discussion and further analysis). The resolved part of the JM region needs to be extended to the membrane. It was modeled here, starting with the MD refined N- and C-terminally extended TM models, c1.1 and c1.2, which were then linked to the JM coiled-coil-like X-ray structure. The TM-JM junction was modeled in order to connect the TM and JM structures with continuing helices. However, we observed constraints during the modeling were imposed by the crossing angle of the TM region. These influence the packing of the junction, which is initially imperfect in one of the two helices in both structures (Fig. 8a).

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.