Clathrin-mediated endocytosis
Clathrin-mediated endocytosis is a
process by which virtually all eukaryotic cells internalize nutrients,
antigens, growth factors, pathogens and recycling receptors (Haucke, 2006).
Internalization may occur either constitutively or in response to certain
stimuli such as in the recycling of synaptic vesicles after exocytosis (Galli
& Haucke, 2001; Jung & Haucke, 2007). The basic mechanisms underlying
endocytosis have fascinated cell biologists for more than two decades, but it
has become clear only recently how clathrin-coated vesicle budding from the
plasma membrane is initiated at the molecular level (fig. 1).
Figure 1: Clathrin-coated vesicle formation and disassembly (taken from Jung
& Haucke, 2007)
We are interested in determining the
exact function of adaptor molecules such as AP-2 in the regulation of
clathrin-coated pit assembly and cargo protein sorting. Recent work from us and
others has shown that PI(4,5)P2 plays
pivotal roles in membrane recruitment via directly binding to AP-2 (Rohde et
al., 2002; Höning et al., 2005) as well as other adaptor proteins and accessory
molecules. During initial assembly of clathrin-coated pits a 'dual-key'
strategy is used that relies on interactions of AP-2 with PI(4,5)P2
and with transmembrane cargo proteins (fig. 2).
Figure 2: 'Dual-key
strategy' used by adaptor proteins for membrane recruitment; taken from Krauss
& Haucke, 2007
Finally,
we have identified stonins as novel adaptor proteins that serve to couple
internalization of presynaptic membrane proteins including synaptotagmin with
AP-2 at endocytic sites (Walther et al., 2001; 2004; Diril et al., 2006; Jung
et al., 2007; fig. 3).
Figure 3: Stonin2-dependent endocytosis of Synaptotagmin1 in transfected
fibroblasts (taken from Diril et al., 2006)
To investigate the function of
clathrin and adaptor molecules in endocytotic vesicle cycling we are using a
combination of biochemical, cell biological, and
genetic tools. We are also developing molecular and genetic tools to
specifically inhibit clathrin-mediated endocytosis at distinct steps of its
cycle (fig.1) in order to investigate the physiological consequences of
impaired membrane trafficking. Much of
this work is performed together with a number of collaborating labs in the
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Created by C.Rodemer, Takustr.6,
Inst.f.Membranbiochemie, 14195 Berlin
Last update Aug,13th,2007