Structural Basis for Different Phosphoinositide Specificities of the PX Domains of Sorting Nexins Regulating G-protein Signaling

Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signaling. A subfamily of PX domain proteins possesses two unique PX-associated domains, as well as a regulator of G protein-coupled receptor signaling (RGS) domain that attenuates G...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-10, Vol.289 (41), p.28554-28568
Main Authors: Mas, Caroline, Norwood, Suzanne J., Bugarcic, Andrea, Kinna, Genevieve, Leneva, Natalya, Kovtun, Oleksiy, Ghai, Rajesh, Ona Yanez, Lorena E., Davis, Jasmine L., Teasdale, Rohan D., Collins, Brett M.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding Sites
Cell Movement
Conserved Sequence
Crystallography, X-Ray
Endosomes - chemistry
Endosomes - metabolism
Escherichia coli - genetics
Escherichia coli - metabolism
Gene Expression
Gene Expression Regulation
GTP-Binding Proteins - genetics
GTP-Binding Proteins - metabolism
HeLa Cells
Humans
Mice
Models, Molecular
Molecular Sequence Data
Phosphatidylinositol Phosphates - chemistry
Phosphatidylinositol Phosphates - metabolism
Protein Structure and Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Sequence Alignment
Signal Transduction
Sorting Nexins - chemistry
Sorting Nexins - genetics
Sorting Nexins - metabolism
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Summary:Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signaling. A subfamily of PX domain proteins possesses two unique PX-associated domains, as well as a regulator of G protein-coupled receptor signaling (RGS) domain that attenuates Gαs-coupled G protein-coupled receptor signaling. Here we delineate the structural organization of these RGS-PX proteins, revealing a protein family with a modular architecture that is conserved in all eukaryotes. The one exception to this is mammalian SNX19, which lacks the typical RGS structure but preserves all other domains. The PX domain is a sensor of membrane phosphoinositide lipids and we find that specific sequence alterations in the PX domains of the mammalian RGS-PX proteins, SNX13, SNX14, SNX19, and SNX25, confer differential phosphoinositide binding preferences. Although SNX13 and SNX19 PX domains bind the early endosomal lipid phosphatidylinositol 3-phosphate, SNX14 shows no membrane binding at all. Crystal structures of the SNX19 and SNX14 PX domains reveal key differences, with alterations in SNX14 leading to closure of the binding pocket to prevent phosphoinositide association. Our findings suggest a role for alternative membrane interactions in spatial control of RGS-PX proteins in cell signaling and trafficking.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.595959