Mechanism of aldolase control of sorting nexin 9 function in endocytosis.
Sorting nexin 9 (SNX9) functions in a complex with the GTPase dynamin-2 at clathrin-coated pits, where it provokes fission of vesicles to complete endocytosis. Here the SNX9.dynamin-2 complex binds to clathrin and adapter protein complex 2 (AP-2) that line these pits, and this occurs through interactions of the low complexity domain (LC4) of SNX9 with AP-2. Intriguingly, localization of the SNX9.dynamin-2 complex to clathrin-coated pits is blocked by interactions with the abundant glycolytic enzyme aldolase, which also binds to the LC4 domain of SNX9. The crystal structure of the LC4 motif of human SNX9 in complex with aldolase explains the biochemistry and biology of this interaction, where SNX9 binds near the active site of aldolase via residues 165-171 that are also required for the interactions of SNX9 with AP-2. Accordingly, SNX9 binding to aldolase is structurally precluded by the binding of substrate to the active site. Interactions of SNX9 with aldolase are far more extensive and differ from those of the actin-nucleating factor WASP with aldolase, indicating considerable plasticity in mechanisms that direct the functions of the aldolase as a scaffold protein.
Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Erumbi S
ES
Rangarajan
HaJeung
H
Park
Emanuelle
E
Fortin
Jurgen
J
Sygusch
Tina
T
Izard
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D034285:Dynamin II / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058305:Sorting Nexins; D050656:Transcription Factor AP-2 / Q000737:chemistry / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry / Q000378:metabolism
D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C400533:SNX9 protein, human; D058305:Sorting Nexins; D050656:Transcription Factor AP-2; D033921:Vesicular Transport Proteins; D051316:Wiskott-Aldrich Syndrome Protein; D034285:Dynamin II; D005634:Fructose-Bisphosphate Aldolase