Book of Abstracts: Albany 2007
June 19-23 2007
Structural basis for the recognition of basic internalization signals within postsynaptic ion channels by AP-2μ
Clathrin-mediated endocytosis is involved in the internalization, recycling, and degradation of cycling membrane receptors, including retrieval of synaptic vesicle membranes and endosomal sorting of postsynaptic ion channels. Many internalized cargo membrane proteins are recognized directly by the clathrin adaptor complex AP-2. We have shown previously that the presynaptic vesicle protein synaptotagmin I1, the GluR2 and GluR3 subunits of AMPA receptors2, and the β3 and γ2 subunits of inhibitory GABAA receptors3 display an AP-2μ -interacting endocytosis signal characterized by a stretch of basic residues. Here we show by combined x-ray crystallography, site-directed mutagenesis and biochemical analysis that basic endocytosis signal derived from the cytoplasmic domains of various pre- and postsynaptic membrane proteins bind to a common site within subdomain B of AP-2μ. Surprisingly, this site precisely overlaps with the binding site within AP-2μ for phosphatidylinositol (4,5)-bisphosphate (PIP2) suggesting a molecular mechanism for how regulated internalization of synaptic membrane proteins may be uncoupled from the co-recognition of PIP2 by AP-2μ4.
A. Vahedi-Faridi* 1
1 Institute of Chemistry and Biochemistry