Adam W. Smith Lab

Molecular Structure and Dynamics in Biological Membranes

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Plexins

Plexins are single-pass transmembrane receptors that bind the axon guidance molecules semaphorins. Single-pass transmembrane proteins are an important class of receptors that display a wide variety of activation mechanisms, often involving ligand-dependent dimerization or conformational changes. Resolving the activation mechanism and dimerization state of these receptors is extremely challenging, especially in a live cell environment.

Plexins_v

We are working to quantify the dimerization state of PlexinA4 and its response to activation by semaphorin binding. Semaphorins are dimeric molecules that activate plexin by binding two copies of plexin simultaneously and inducing formation of a specific active dimer of plexin. An open question is if there are pre-existing plexin dimers that could act as autoinhibitory complexes.  We address these questions with Pulsed Interleaved Excitation Fluorescence Cross-correlation Spectroscopy (PIE-FCCS). By comparing the cross-correlation of full-length PlexinA4 to control proteins and plexin mutants, we show that dimerization of inactive PlexinA4 requires the Sema domain, but not the cytoplasmic domain.

Plexin Mutants

Ligand stimulation with Sema6A does not change the degree of cross-correlation, indicating that plexin activation does not lead to higher-order oligomerization. Together, the results suggest that semaphorin activates plexin by disrupting an inhibitory plexin dimer and inducing the active dimer.

Marita, M., Wang, Y, Comar, W. D., Shi, X., Dasari, P., Zhang, X., and Smith, A. W. (2015) Class A plexins are organized as preformed inactive dimers on the cell surface. Biophysical Journal 109, 1937-1945.

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