Sorting nexins (SNXs) are a family of proteins that involved in diverse intracellular endosomal trafficking pathways. They all contain a PX (phox-homology) domain. The PX domain, via binding to certain phosphoinositide lipids, is responsible for membrane attachment to organelles of the endosomal system. The PX domain mostly binds to PtdIns3P, although other specificities have been reported for a few SNXs.
It was previously reported that over expression of SNX10 could induce the formation of giant vacuoles in mammalian cells. Furthermore, an SNX10/V-ATPase regulated vesicular trafficking pathway was identified to be crucial during early embryonic development. More recently, several mutations in SNX10 have been linked to osteopetrosis. Meanwhile, SNX11, a close homologue of SNX10, was found to be able to inhibit SNX10-induced vacuolation. We recently reported the crystal structure of SNX11 and proposed a novel extended PX domain. The intact Pxe domain is responsible for SNX11 inhibitory activity against SNX10-induced vacualation. Our structual study on SNX10 revealed a second member of the PXe domain. From the structure, we can identify the disease-related mutations on SNX10. Some of the mutations also affect SNX10 ability to incude vacualation. Taken together, our study reveals insights into SNX10 role in human autosomal recessive osteopetrosis.