PMID: 20881961

 

    Legend: Gene, Sites

Title : Structural basis for semaphorin signalling through the plexin receptor

Abstract :

1. Semaphorins and their receptor plexins constitute a pleiotropic cell-signalling system that is used in a wide variety of biological processes, and both protein families have been implicated in numerous human diseases
2. The binding of soluble or membrane-anchored semaphorins to the membrane-distal region of the plexin ectodomain activates plexin 's intrinsic GTPase-activating protein ( GAP ) at the cytoplasmic region , ultimately modulating cellular adhesion behaviour
3. However, the structural mechanism underlying the receptor activation remains largely unknown
4. Here we report the crystal structures of the semaphorin 6A ( Sema6A ) receptor-binding fragment and the plexin A2 ( PlxnA2 ) ligand-binding fragment in both their pre-signalling (that is, before binding) and signalling (after complex formation) states
5. Before binding, the Sema6A ectodomain was in the expected 'face-to-face' homodimer arrangement, similar to that adopted by Sema3A and Sema4D , whereas PlxnA2 was in an unexpected 'head-on' homodimer arrangement
6. In contrast, the structure of the Sema6A- PlxnA2 signalling complex revealed a 2:2 heterotetramer in which the two PlxnA2 monomers dissociated from one another and docked onto the top face of the Sema6A homodimer using the same interface as the head-on homodimer , indicating that plexins undergo 'partner exchange'
7. Cell-based activity measurements using mutant ligands/receptors confirmed that the Sema6A face-to-face dimer arrangement is physiologically relevant and is maintained throughout signalling events
8. Thus , homodimer-to-heterodimer transitions of cell-surface plexin that result in a specific orientation of its molecular axis relative to the membrane may constitute the structural mechanism by which the ligand-binding 'signal' is transmitted to the cytoplasmic region , inducing GAP domain rearrangements and activation

Output (sent_index, trigger, protein, sugar, site):

Output(Part-Of) (sent_index, protein, site):

• 2. plexin, ectodomain
• 4. Sema6A, fragment
• 4. plexin A2, fragment
• 4. receptor, fragment
• 4. semaphorin 6A, fragment
• 5. Sema6A, ectodomain
• 6. Sema6A homodimer, face

*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

Protein	NCBI ID	SENTENCE INDEX
Sema3A	10371	5
semaphorin 6A	57556	4
Sema6A homodimer	57556	6
PlxnA2	5362	4,5,6
plexin A2	5362	4
structure of the Sema6A	57556	6
Sema4D	10507	5
Sema6A	57556	4,5,7