Abstract
Vacuolar protein sorting protein 29 (Vps29p), which is involved in retrograde trafficking from prevacuolar endosomes to the trans-Golgi network, performs its biological functions by participating in the formation of a "retromer complex." In human cells, this complex comprises four conserved proteins: hVps35p, hVps29p, hVps26p, and sorting nexin 1 protein (SNX1). Here, we report the crystal structure of hVps29p at 2.1 Angstroms resolution, the first three-dimensional structure of the retromer subunits. This novel structure adopts a four-layered alpha-beta-beta-alpha sandwich fold. hVps29p contains a metal-binding site that is very similar to the active sites of some proteins of the phosphodiesterase/nuclease protein family, indicating that hVps29p may carry out chemically similar functions. Structure and sequence conservation analysis suggests that hVps29p contains two protein-protein interaction sites. One site, which potentially serves as the interface between hVps29p and hVps35p, comprises 5 conserved hydrophobic and 8 hydrophilic residues. The other site is relatively more hydrophilic and may serve as a binding interface with hVps26p, SNX1, or other target proteins.
Highlights
Vacuolar protein sorting protein 29 (Vps29p), which is involved in retrograde trafficking from prevacuolar endosomes to the trans-Golgi network, performs its biological functions by participating in the formation of a “retromer complex.” In human cells, this complex comprises four conserved proteins: hVps35p, hVps29p, hVps26p, and sorting nexin 1 protein (SNX1)
Interaction of hVps29p with hVps35p and Other Target Proteins—Previous research suggests that hydrophobic interactions serve as the major sources of protein folding and protein stabilization (46 – 48) and the predominant driving force in the formation of biologically relevant complexes [45, 49]
Hydrophilic interactions participate in stabilizing protein complexes by providing strong interactions and shielding the hydrophobic core from hydrophilic environments [50, 51]
Summary
Vacuolar protein sorting; Vps29p, these Vps genes are involved directly or indirectly in protein sorting or trafficking between the late Golgi and the vacuoles (4 – 6). SNX1 contains a Phox homology domain that can bind to phosphatidylinositol-3-phosphate, phosphatidylinositol 3,5-bisphosphate, or phosphatidylinositol 3,4,5-bisphosphate These phosphoinositides may serve as direct, local regulators and recruiters of protein machinery that control membrane trafficking in some pathways, whereas the exact roles of the three small molecules in the retromer complex remain to be investigated (20 –23). Northern blot analyses show that mRNA of hVps is expressed highly in the colon, thymus, spleen, and peripheral leukocytes, whereas mRNAs of hVps and hVps are expressed much lower in these tissues [17] These data suggest that hVps29p serves as a subunit of the retromer complex and carries out other biological roles [17]. Based on the structural and sequence analysis, two conserved surface regions are proposed to serve as binding sites for hVps35p and other target proteins, respectively
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