Clathrin-mediated endocytosis is a major route for the internalisation of plasma membrane (PM) proteins and involves their interactions with endocytic adaptors through sorting signals such as the NPFxD motif. It remains unclear though whether these signals also have an active role in the recruitment of adaptor proteins to the PM. In their study, Santiago Di Pietro and colleagues (Tolsma et al., 2020) now analyse in detail the role of the NPFxD signal in the recruitment of the budding yeast adaptor Sla1, which binds to this motif through its SHD1 domain and to endocytic coat proteins via its C-terminal SR domain. The authors first generated a series of point mutations within the SHD1 domain that affect the NPFxD-binding surface to show that these cause a proportional decrease in Sla1 recruitment to endocytic sites. Furthermore, combination of the most-severe SHD1 point mutation with SR domain deletion results in a complete loss of PM recruitment, suggesting that multiple interactions contribute to PM localisation of Sla1. Sla1 also contains a SH3 domain, which can bind to ubiquitin in vitro – this has been suggested as an alternative means of recruitment to ubiquitylated PM proteins. Indeed, a Sla1 fragment comprising the SHD1 domain and this SH3 domain efficiently localised to the PM. This study thus provides new insights into the molecular basis of adaptor recruitment to integral PM protein cargoes, lending further support to the notion of a more active role of the cargo in mediating its own internalisation.
How cargoes recruit their endocytic adaptor
How cargoes recruit their endocytic adaptor. J Cell Sci 1 October 2020; 133 (19): e1905. doi:
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