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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.


Models for plexin-B1 trimer TM region before (a,c) and after the simulations (b,d).Models with clockwise (a,c) and anti-clockwise (b,d) helix packing, looking from N-terminus into membrane. Helix A is on upper side, then B and C clockwise for clockwise, C and B for anti-clockwise. Ser and Thr sidechains are shown in stick (orange) and location of small residues (AxxxGxxxG) in the center of the TM region are indicated (in yellow).
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pone.0121513.g005: Models for plexin-B1 trimer TM region before (a,c) and after the simulations (b,d).Models with clockwise (a,c) and anti-clockwise (b,d) helix packing, looking from N-terminus into membrane. Helix A is on upper side, then B and C clockwise for clockwise, C and B for anti-clockwise. Ser and Thr sidechains are shown in stick (orange) and location of small residues (AxxxGxxxG) in the center of the TM region are indicated (in yellow).

Mentions: The intracellular region of plexin-B1 has been crystallized in a trimeric state when bound to the small GTPase Rac1 [22]. It is important to test which configuration of the TM region would be compatible with a trimeric structure. Two TM trimer models, a left-hand/clockwise and a right-hand/anti-clockwise arrangement, were built and equilibrated for 1.0 μs on Anton. The initial and final structures are shown in Fig. 5 (and Fig. A in S1 File). Changes in the rotation angle for both clockwise and anti-clockwise helix trimer structures during the simulations are shown in Fig. B in S1 File. As can be seen, both the clockwise and anticlockwise structures are stable during this extensive simulation. There is a larger initial rotation at the contacting interface for helix C in the clockwise structure (left panel of Fig. B in S1 File) and this helix continues to fluctuate. Similar fluctuations are seen in helix A of the anti-clockwise structure.


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)

Models for plexin-B1 trimer TM region before (a,c) and after the simulations (b,d).Models with clockwise (a,c) and anti-clockwise (b,d) helix packing, looking from N-terminus into membrane. Helix A is on upper side, then B and C clockwise for clockwise, C and B for anti-clockwise. Ser and Thr sidechains are shown in stick (orange) and location of small residues (AxxxGxxxG) in the center of the TM region are indicated (in yellow).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121513.g005: Models for plexin-B1 trimer TM region before (a,c) and after the simulations (b,d).Models with clockwise (a,c) and anti-clockwise (b,d) helix packing, looking from N-terminus into membrane. Helix A is on upper side, then B and C clockwise for clockwise, C and B for anti-clockwise. Ser and Thr sidechains are shown in stick (orange) and location of small residues (AxxxGxxxG) in the center of the TM region are indicated (in yellow).
Mentions: The intracellular region of plexin-B1 has been crystallized in a trimeric state when bound to the small GTPase Rac1 [22]. It is important to test which configuration of the TM region would be compatible with a trimeric structure. Two TM trimer models, a left-hand/clockwise and a right-hand/anti-clockwise arrangement, were built and equilibrated for 1.0 μs on Anton. The initial and final structures are shown in Fig. 5 (and Fig. A in S1 File). Changes in the rotation angle for both clockwise and anti-clockwise helix trimer structures during the simulations are shown in Fig. B in S1 File. As can be seen, both the clockwise and anticlockwise structures are stable during this extensive simulation. There is a larger initial rotation at the contacting interface for helix C in the clockwise structure (left panel of Fig. B in S1 File) and this helix continues to fluctuate. Similar fluctuations are seen in helix A of the anti-clockwise structure.

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.