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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.


The final structures for plexin-B1 models b1.1, b1.2 and b1.3 after all-atom MD simulation.The geometric parameters for the final structures are shown in Fig. 3b. The first AxxxGxxxG dimerization motif is shown in yellow, the alternate motif, QxxxGxxxS in cyan. Models b1.1 and b1.2 are right-handed and b1.3 is left handed.
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pone.0121513.g004: The final structures for plexin-B1 models b1.1, b1.2 and b1.3 after all-atom MD simulation.The geometric parameters for the final structures are shown in Fig. 3b. The first AxxxGxxxG dimerization motif is shown in yellow, the alternate motif, QxxxGxxxS in cyan. Models b1.1 and b1.2 are right-handed and b1.3 is left handed.

Mentions: Looking at some of the simulations in greater detail, Figs. 2 and 4 show results for the MD refinement of the plexin-B1 models 1–3. In Fig. 2 the geometric parameters are plotted as a function of simulation time, illustrating that there are only few significant configurational fluctuations in crossing (Fig. 2b, middle panel) and relative rotation angles (Fig. 2a, lower panel). By 1.0 μs (and in case of b1.1 by 2.0 μs) the simulations are rather well converged in that the changes appear complete, giving us confidence that generally this time is sufficient to equilibrate the structures. In Fig. 4 the final structures for b1.1, b1.2 and b1.3 are shown, which includes both clockwise/right-handed (b1.1 and b1.2) and anti-clockwise/left-handed (b1.3) helix dimer structures. Here, the helices interact via two alternate sets of GxxxG-like motifs. The details of interactions stabilizing the structures, the extent of the observed fluctuations over the last 250 ns of the simulations and the likely functional consequences are discussed below.


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)

The final structures for plexin-B1 models b1.1, b1.2 and b1.3 after all-atom MD simulation.The geometric parameters for the final structures are shown in Fig. 3b. The first AxxxGxxxG dimerization motif is shown in yellow, the alternate motif, QxxxGxxxS in cyan. Models b1.1 and b1.2 are right-handed and b1.3 is left handed.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121513.g004: The final structures for plexin-B1 models b1.1, b1.2 and b1.3 after all-atom MD simulation.The geometric parameters for the final structures are shown in Fig. 3b. The first AxxxGxxxG dimerization motif is shown in yellow, the alternate motif, QxxxGxxxS in cyan. Models b1.1 and b1.2 are right-handed and b1.3 is left handed.
Mentions: Looking at some of the simulations in greater detail, Figs. 2 and 4 show results for the MD refinement of the plexin-B1 models 1–3. In Fig. 2 the geometric parameters are plotted as a function of simulation time, illustrating that there are only few significant configurational fluctuations in crossing (Fig. 2b, middle panel) and relative rotation angles (Fig. 2a, lower panel). By 1.0 μs (and in case of b1.1 by 2.0 μs) the simulations are rather well converged in that the changes appear complete, giving us confidence that generally this time is sufficient to equilibrate the structures. In Fig. 4 the final structures for b1.1, b1.2 and b1.3 are shown, which includes both clockwise/right-handed (b1.1 and b1.2) and anti-clockwise/left-handed (b1.3) helix dimer structures. Here, the helices interact via two alternate sets of GxxxG-like motifs. The details of interactions stabilizing the structures, the extent of the observed fluctuations over the last 250 ns of the simulations and the likely functional consequences are discussed below.

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.