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PDB:3al8

Protein Name

Semaphorin 6A/Plexin A2 complex

Species

mouse (Mus musculus)

Biological Context

Semaphorins are a large family of cell surface or secreted proteins. Semaphorins were first identified as repellent guidance cues that assist axon pathfinding to target neurons during neuronal development. It is known that the repulsive semaphorin signal is transduced by the plexin receptors on neuron. Semaphorins and plexins share a common Sema domain in the N-terminal extracellular region and interact with one another through the Sema domains during the signal transduction. The binding of semaphorin to the extracellular face of plexin activates its intrinsic GTPase-activating protein (GAP) activity residing in the cytoplasmic region, ultimately mediating axon repulsive behavior.

It is now accepted that the semaphorins and plexins constitute a pleiotropic cell-signaling system involved in a wide variety of biological processes. For instance, several classes of semaphorins play crucial roles in modulation of various immune responses. It is also reported that angiogenesis, cardiogenesis, and bone homeostasis are also regulated by semaphorin-plexin signaling. Furthermore, the malfunction of the semphorin-plexin signaling has been implicated in various human diseases such as tumor progression, autoimmune diseases, atopic dermatitis and so on.

Structure Description

3al83al8_x3al8_y

Semaphorins are a large family of cell surface or secreted proteins. Semaphorins were first identified as repellent guidance cues that assist axon pathfinding to target neurons during neuronal development. It is known that the repulsive semaphorin signal is transduced by the plexin receptors on neuron. Semaphorins and plexins share a common Sema domain in the N-terminal extracellular region and interact with one another through the Sema domains during the signal transduction. The binding of semaphorin to the extracellular face of plexin activates its intrinsic GTPase-activating protein (GAP) activity residing in the cytoplasmic region, ultimately mediating axon repulsive behavior.

It is now accepted that the semaphorins and plexins constitute a pleiotropic cell-signaling system involved in a wide variety of biological processes. For instance, several classes of semaphorins play crucial roles in modulation of various immune responses. It is also reported that angiogenesis, cardiogenesis, and bone homeostasis are also regulated by semaphorin-plexin signaling. Furthermore, the malfunction of the semphorin-plexin signaling has been implicated in various human diseases such as tumor progression, autoimmune diseases, atopic dermatitis and so on.

Crystal structures of the Sema plus PSI segment of seaphorin 6A (Sema6A) and plexin A2 (PlxnA2) are shown in Fig. 1.

Fig.1 Individual propeller blades of the Sema domain are colored differently. Extrusions and bulge are highlighted in black and red, respectively.

In both proteins, the sema domain displays a seven-bladed beta-propeller fold with two characteristic insertions. One is present between the blades 1 and 2 and the second is found in the middle of the blade 5 (termed as "extrusions 1 and 2", respectively). In addition, PlxnA2 contains another unique insertion within the blade 3. This insertion makes a characteristically prominent protrusion from the side of the beta-propeller and is therefore termed as "bulge". The PSI domain, which is located at the side of the blade 6 of the Sema domain, shows a small globular structure knotted with conserved disulfide bonds.

The extracellular segments of Sema6A and PlxnA2 constitute a 2:2 heterotetrameric complex as shown in Fig. 2.

Fig.2 Sema6A and PlxnA2 form a 2:2 heterotetrameric complex. Two Sema6A molecules show a face-to-face homodimeric structure in the complex while two PlxnA2 molecules individually dock onto the two Sema6A molecules.

In this complex, two Sema6A molecules form a homodimer in a face-to-face orientation while two PlxnA2 molecules independently dock onto the two Sema6A monomers. Interestingly, Sema6A and PlxnA2 use the same face of the beta-propeller for the heterophilic interaction. The above-mentioned extrusions 1 and 2 largely contribute to the heterophilic interaction, and the bulge of PlxnA2 is also located at the heart of the interface. The 2:2 stoichiometry and the relative orientation of semaphorin and plexin are conserved among all available crystal structures including the Sema4D/PlxnB1 and Sema7A/PlxnC1 complexes. Thus, it is highly probable that the heterotetrameric configuration is common in all semaphorin/plexin pairs.

Several models have been proposed for the plexin activation mechanism based on the 2:2 heterotetrameric complex, which can be categorized into two models; One is the receptor-clustering model and the other is the receptor-reorientation model. Janssen, B. et al. argued that the binding of semaphorin induces plexin-to-plexin cis interaction through the stalk region in the extracellular region, which would seed further oligomerization among the semaphorin-plexin complexes. In contrast, Nogi, T. et al. argued that the formation of the 2:2 complex alters the configuration of the GAP domain and modulates the activity. The authors reported that PlxnA2 could form a homodimer in the pre-signaling state. As shown in Fig. 3, transition from homodimer of plexin to the semaphorin-engaged heterotetrameric complex might directly change the dimeric state of the GAP domain at the cytoplasmic side. Liu, H. et al. also reported in the structural study on the Sema7A/PlxnC1 complex that the extracellular domain of PlxnC1 exists as a mixture of oligomeric states. The authors argued that Semaphorin-induced rearrangement of plexin dimer with a particular molecular orientation might be the means of receptor activation.

Fig.3 Transition from the head-on cis homodimer of plexin (left) to the semaphorin-engaged complex (right) changes the relative orientation of the plexin molecular axis. This conformational change is transmitted through the stalk region and alters the dimeric state of the cytoplasmic GAP domain, which results in signal initiation.

Protein Data Bank (PDB)

References

Source

  • Nogi, T. Yasui, N. Mihara, E. Matsunaga, Y. Noda, M. Yamashita, N. Toyofuku, T. Uchiyama, S. Goshima, Y. Kumanogoh, A. Takagi, J.; "Structural basis for semaphorin signalling through the plexin receptor."; Nature; (2010) 467:1123-1127 PubMed:20881961.

Others

author: Terukazu NOGI


Japanese version:PDB:3al8