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Published online 13 August 2001. doi:10.1083/jcb.200103040
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© The Rockefeller University Press, 0021-9525/2001/8/857 $5.00
The Journal of Cell Biology, Volume 154, Number 4, August 20, 2001 857-866

Article

The AP2 binding site of synaptotagmin 1 is not an internalization signal but a regulator of endocytosis



Nadine Jarousse and Regis B. Kelly

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143

Address correspondence to Regis B. Kelly, Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448. Tel.: (415) 476-4095. Fax: (415) 502-5145. E-mail: rkelly{at}biochem.ucsf.edu

One characteristic linking members of the synaptotagmin family to endocytosis is their ability to bind the heterotetrameric AP2 complex via their C2B domain. By using CD4/synaptotagmin 1 chimeras, we found that the internalization signal of synaptotagmin 1 lies at the extreme COOH-terminus of the protein and can function in the absence of the C2B domain that contains the AP2 binding site. However, although not essential for internalization, the C2B domain of synaptotagmin 1 appeared to control the recognition of the internalization motif. By mutagenesis, two sites have been identified that modify regulation by the C2B domain in the neuroendocrine PC12 cell line. Mutation of a dilysine motif in the ß sandwich core of the domain eliminates endocytosis. This site is known to be a site of protein–protein interaction. Mutations in the calcium binding region, or in its close proximity, also affect internalization in PC12 cells. In fibroblasts, the C2B domain inhibits the COOH-terminal internalization signal, resulting in an absence of internalization in those cells. Thus, internalization of synaptotagmin 1 is controlled by the presence of a latent internalization signal in the COOH-terminal region and a regulatory region in the C2B domain. We propose that internalization of synaptotagmin 1 is regulated in this way to allow it to couple the processes of endocytosis and calcium-mediated exocytosis in cells of the neuroendocrine lineage.

Key Words: synaptotagmin; endocytosis; internalization signal; AP2 adaptor; synaptic vesicle


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