Modeling Transmembrane Domain Dimers/Trimers of Plexin Receptors: Implications for Mechanisms of Signal Transmission across the Membrane

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.

Rnd3-induced cell rounding requires interaction with Plexin-B2

“…Plexin-B1 dimerizes when it binds to its dimeric Sema4D ligand, and dimerization is required for Sema4D-induced signalling (Janssen et al, 2010). However, plexin-B2 is predicted not to form stable dimers as a result of the presence of transmembrane prolines (Zhang et al, 2015). Signalling by plexin-B2 must therefore be different to that of plexin-B1.…”

Different dynamics and pathway of disulfide bonds reduction of two human defensins, a molecular dynamics simulation study

“…In recent years, molecular dynamics simulations have been proven to be a useful tool to understand the structure, dynamics and functional mechanism of proteins . Researchers have worked on the biophysical aspects of disulfide bonds containing proteins, and the link between conformational folding and disulfide bond formation/rupture using simulation method.…”

“…In recent years, molecular dynamics simulations have been proven to be a useful tool to understand the structure, dynamics and functional mechanism of proteins. [22][23][24] Researchers have worked on the biophysical aspects of disulfide bonds containing proteins, and the link between conformational folding and disulfide bond formation/rupture using simulation method. Qin et al 25 found that the formation of specific collapsed native-like structures guides efficient folding of disulfide bonds using coarse-grained molecular simulations.…”

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

“…The TMD is therefore critically important in transmitting signals from the external environment to the inside of the cell, with many recent investigations exploring the mechanism by which TMD interactions regulate cell signaling (2)(3)(4)(5)(6). TMDs of single-pass membrane receptors have been shown to cluster, resulting in homotypic and/or heterotypic interactions, with TMDs often forming not only homo-and/or heterodimers but higher-order oligomers in cell membranes (7)(8)(9)(10). Most investigations of TMD interactions have analyzed homo-oligomerization in vitro and in vivo, with fewer to date assessing heterotypic TMD associations.…”