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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.


Related in: MedlinePlus

Schematic illustrating that structures with like-topology can be connected via straight segments, while unlike structures require some bending, either of irregular or of helical structures.
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pone.0121513.g009: Schematic illustrating that structures with like-topology can be connected via straight segments, while unlike structures require some bending, either of irregular or of helical structures.

Mentions: Firstly, one may consider the lateral distances and the rotation between the N- and C-termini of the TM helices as they enter/exit the membrane. In case of the TM trimer or largely parallel dimers, a modest amount of bulging would occur if unlike structures are connected. Nevertheless, the relative rotation of the TM (and especially JM) helices is similar in the plexin-B1 TM-JM trimer structures, suggesting that by contrast to the plexin-B1 dimers, the signaling mechanism would involve formation/dissociation of the TM-JM trimers, possibly via dimer intermediates. In the case of the two plexin-C1 TM-JM structures, the TM region differ more dramatically; in the parallel/slightly RH structure, the helices cross near Val21, with both sidechains at the interface. The bulged RH crossed structure, by contrast has the bulged helix rotated by ~ 180o forming a back-to-back packing arrangement. In the JM coiled–coil, not only is the crossing angle different, but the bulged helix is also translated about 1 turn upwards and rotated by ~ 90o, relative to the parallel structure. This difference suggests a piston-like mechanism for TM signaling depicted in Fig. 1a, together with a rotation and separation of the intracellular plexin-C1 domains in the bulged/RH crossed structure. Overall, considering the number of contacts, the near parallel structure could be the more stable one by itself. However, larger lateral differences occur between parallel and crossed structures, as illustrated by plexin-C1. Here the distances between the TM-JM junctions of model1 and 2 are 11 Å and 23 Å, respectively—23 Å is sufficient to have 4.3 helical turns in an antiparallel helix coiled-coil arrangement for the JM region, similar to the example of EGFR [30]. Generally connecting like-structures (e.g. RH crossed helices with clockwise coiled-coils) results in more close-packed and less bulged structures than connecting unlike TM-JM structures as illustrated in Fig. 9.


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)

Schematic illustrating that structures with like-topology can be connected via straight segments, while unlike structures require some bending, either of irregular or of helical structures.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121513.g009: Schematic illustrating that structures with like-topology can be connected via straight segments, while unlike structures require some bending, either of irregular or of helical structures.
Mentions: Firstly, one may consider the lateral distances and the rotation between the N- and C-termini of the TM helices as they enter/exit the membrane. In case of the TM trimer or largely parallel dimers, a modest amount of bulging would occur if unlike structures are connected. Nevertheless, the relative rotation of the TM (and especially JM) helices is similar in the plexin-B1 TM-JM trimer structures, suggesting that by contrast to the plexin-B1 dimers, the signaling mechanism would involve formation/dissociation of the TM-JM trimers, possibly via dimer intermediates. In the case of the two plexin-C1 TM-JM structures, the TM region differ more dramatically; in the parallel/slightly RH structure, the helices cross near Val21, with both sidechains at the interface. The bulged RH crossed structure, by contrast has the bulged helix rotated by ~ 180o forming a back-to-back packing arrangement. In the JM coiled–coil, not only is the crossing angle different, but the bulged helix is also translated about 1 turn upwards and rotated by ~ 90o, relative to the parallel structure. This difference suggests a piston-like mechanism for TM signaling depicted in Fig. 1a, together with a rotation and separation of the intracellular plexin-C1 domains in the bulged/RH crossed structure. Overall, considering the number of contacts, the near parallel structure could be the more stable one by itself. However, larger lateral differences occur between parallel and crossed structures, as illustrated by plexin-C1. Here the distances between the TM-JM junctions of model1 and 2 are 11 Å and 23 Å, respectively—23 Å is sufficient to have 4.3 helical turns in an antiparallel helix coiled-coil arrangement for the JM region, similar to the example of EGFR [30]. Generally connecting like-structures (e.g. RH crossed helices with clockwise coiled-coils) results in more close-packed and less bulged structures than connecting unlike TM-JM structures as illustrated in Fig. 9.

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.


Related in: MedlinePlus