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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.

Original publication

DOI

10.1098/rsob.160053

Type

Journal article

Journal

Open Biol

Publication Date

05/2016

Volume

6

Keywords

X-ray crystallography, astrotactin-2, biophysical interaction analysis, membrane attack complex-perforin protein, neural migration control, Animals, Cell Membrane, Crystallography, X-Ray, Glycoproteins, HEK293 Cells, Humans, Inositol Phosphates, Models, Molecular, Nerve Tissue Proteins, Neurogenesis, Phylogeny, Protein Binding, Protein Domains, Protein Structure, Secondary, Protein Structure, Tertiary, Vertebrates