Structure of astrotactin 2: a conserved vertebrate specific and perforin like membrane protein involved in neuronal development
The vertebrate specific proteins astrotactin 1 and 2 (ASTN 1 and ASTN 2) are integral membrane perforin like proteins known to play critical roles in neurodevelopment, while ASTN 2 has been linked to the planar cell polarity pathway in hair cells. Genetic variations associated with them are linked to a variety of neurodevelopmental disorders and other neurological pathologies, including an advanced onset of Alzheimer's disease. Here we present the structure of the majority endosomal region of ASTN 2, showing it to consist of a unique combination of polypeptide folds: a perforin like domain, a minimal epidermal growth factor like module, a unique form of fibronectin type III domain and an annexin like domain. The perforin like domain differs from that of other members of the membrane attack complex perforin (MACPF) protein family in ways that suggest ASTN 2 does not form pores. Structural and biophysical data show that ASTN 2 (but not ASTN 1) binds inositol triphosphates, suggesting a mechanism for membrane recognition or secondary messenger regulation of its activity. The annexin like domain is closest in fold to repeat three of human annexin V and similarly binds calcium, and yet shares no sequence homology with it. Overall, our structure provides the first atomic resolution description of a MACPF protein involved in development, while highlighting distinctive features of ASTN 2 responsible for its activity.
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