A molecular code for endosomal recycling of phosphorylated cargos by the SNX27-retromer complex.
Recycling of internalized receptors from endosomal compartments is essential for the receptors' cell-surface homeostasis. Sorting nexin 27 (SNX27) cooperates with the retromer complex in the recycling of proteins containing type I PSD95-Dlg-ZO1 (PDZ)-binding motifs. Here we define specific acidic amino acid sequences upstream of the PDZ-binding motif required for high-affinity engagement of the human SNX27 PDZ domain. However, a subset of SNX27 ligands, such as the β2adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor, lack these sequence determinants. Instead, we identified conserved sites of phosphorylation that substitute for acidic residues and dramatically enhance SNX27 interactions. This newly identified mechanism suggests a likely regulatory switch for PDZ interaction and protein transport by the SNX27-retromer complex. Defining this SNX27 binding code allowed us to classify more than 400 potential SNX27 ligands with broad functional implications in signal transduction, neuronal plasticity and metabolite transport.
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Thomas
T
Clairfeuille
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Caroline
C
Mas
Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands, Western Australia, Australia.
Audrey S M
AS
Chan
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Zhe
Z
Yang
Lipid Signaling Laboratory, Centro Nacional de Biotecnología, Madrid, Spain.
Maria
M
Tello-Lafoz
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Mintu
M
Chandra
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia.
Jocelyn
J
Widagdo
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Markus C
MC
Kerr
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Blessy
B
Paul
Lipid Signaling Laboratory, Centro Nacional de Biotecnología, Madrid, Spain.
Isabel
http://orcid.org/0000-0003-2762-6241
I
Mérida
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Rohan D
http://orcid.org/0000-0001-7455-5269
RD
Teasdale
Cellular Orthopaedic Laboratory, School of Surgery, University of Western Australia, Nedlands, Western Australia, Australia.
Nathan J
NJ
Pavlos
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia.
Victor
http://orcid.org/0000-0002-4062-4884
V
Anggono
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Brett M
BM
Collins
D000595:Amino Acid Sequence; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D054731:PDZ Domains; D010766:Phosphorylation; D011485:Protein Binding; D060066:Protein Interaction Maps; D021381:Protein Transport; D017470:Receptors, Glutamate / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D058305:Sorting Nexins / Q000737:chemistry / Q000378:metabolism*
D017470:Receptors, Glutamate; C522885:SNX27 protein, human; D058305:Sorting Nexins