Extracellular regulation of type IIa receptor protein tyrosine phosphatases: mechanistic insights from structural analyses

• Type IIa RPTPs are neuronal signalling hubs.
• Extensive flexibility of RPTP ectodomains is revealed by recent structural studies.
• Crystal structures explain type IIa RPTP-ligand interaction specificities.
• Proteoglycan and protein ligands compete for type IIa RPTP binding.
• Novel mechanisms for neuronal RPTP regulation uncovered by structural analyses.

The receptor protein tyrosine phosphatases (RPTPs) exhibit a wide repertoire of cellular signalling functions. In particular, type IIa RPTP family members have recently been highlighted as hubs for extracellular interactions in neurons, regulating neuronal extension and guidance, as well as synaptic organisation. In this review, we will discuss the recent progress of structural biology investigations into the architecture of type IIa RPTP ectodomains and their interactions with extracellular ligands. Structural insights, in combination with biophysical and cellular studies, allow us to begin to piece together molecular mechanisms for the transduction and integration of type IIa RPTP signals and to propose hypotheses for future experimental validation.