Sorting out the cellular functions of sorting nexins

Sorting nexins (SNXs) are 400–700 amino-acid hydrophilic proteins that are characterized by the presence of a phospholipid-binding domain, the PX domain. In addition to the PX domain, SNXs have various protein–protein interaction motifs that might determine their subcellular localization or their ability to form specific complexes. On the basis of common domain structures, the SNX family of proteins can be divided into three subgroups. The first group, which contains SNX1 and SNX2, has long carboxy-terminal extensions containing 1–3 coiled-coil domains that might be involved in homo- and/or hetero-oligomerization with other SNXs, as well as other protein–protein interactions. The second group is formed by SNX3 and related SNXs, which seem to have only a PX domain. The remaining SNXs, which form the third group, have a variety of protein–protein interaction, membrane targeting or G-protein regulatory sequences. The structure of the PX domain of p40phox revealed a novel protein fold and mutational analysis identified several residues that are involved in stabilizing the binding of PtdIns(3)P to p40phox. Studies of the structure of the p47phox PX domain showed that SH3-domain interactions might regulate PX-domain function. Structural analysis of the PX domain of Vam7 showed that the membrane-targeting ability of the Vam7 PX domain might involve both a specific basic PtdIns-binding pocket, as well as nonspecific hydrophobic interactions between loop residues and the membrane. The functions of yeast nexins are relatively well established. Vps5, the yeast homologue of SNX1 and SNX2, is important for vacuolar trafficking and carries out its function by assembling into a so-called retromer complex. Grd19, which is related to SNX3, seems to have a function in the pre-vacuolar compartment. Mvp1, the yeast homologue for SNX8, might be involved in sorting proteins in the late Golgi for delivery to the vacuole, as well as the retrieval of proteins from the pre-vacuolar endosomes to the late Golgi. Mammalian SNXs are thought to be important for the sorting of proteins in the endosomal pathway but possibly also in sorting vesicles that are not derived from the plasma membrane. The challenge for future research will be to identify the specific functions of individual SNXs, and to study the cellular regulation of these molecules.