Determinants of the endosomal localization of sorting nexin 1.
The sorting nexin (SNX) family of proteins is characterized by sequence-related phox homology (PX) domains. A minority of PX domains bind with high affinity to phosphatidylinositol 3-phosphate [PI(3)P], whereas the majority of PX domains exhibit low affinity that is insufficient to target them to vesicles. SNX1 is located on endosomes, but its low affinity PX domain fails to localize in vivo. The NMR structure of the PX domain of SNX1 reveals an overall fold that is similar to high-affinity PX domains. However, the phosphatidylinositol (PI) binding pocket of the SNX1 PX domain is incomplete; regions of the pocket that are well defined in high-affinity PX domains are highly mobile in SNX1. Some of this mobility is lost upon binding PI(3)P. The C-terminal domain of SNX1 is a long helical dimer that localizes to vesicles but not to the early endosome antigen-1-containing vesicles where endogenous SNX1 resides. Thus, the obligate dimerization of SNX1 that is driven by the C-terminal domain creates a high-affinity PI binding species that properly targets the holo protein to endosomes.
Zhong
Qi
Q
Department of Medicine and Cellular, University of California, San Diego, La Jolla, 92093-0650, USA.
Watson
Martin J
MJ
Lazar
Cheri S
CS
Hounslow
Andrea M
AM
Waltho
Jonathan P
JP
Gill
Gordon N
GN
D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D002352:Carrier Proteins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D010716:Phosphatidylinositols; D017346:Protein Serine-Threonine Kinases; D033921:Vesicular Transport Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases