A molecular code for endosomal recycling of phosphorylated cargos by the SNX27–retromer complex

Clairfeuille, Thomas, Mas, Caroline, Chan, Audrey S. M., Yang, Zhe, Tello-Lafoz, Maria, Chandra, Mintu, Wigagdo, Jocelyn, Kerr, Markus, Blessy, Paul, Merida, Isabel, Teasdale, Rohan D., Pavlos, Nathan J., Anggono, Victor and Collins, Brett (2016) A molecular code for endosomal recycling of phosphorylated cargos by the SNX27–retromer complex. Nature Structural and Molecular Biology, 23 10: 921-932. doi:10.1038/nsmb.3290

Author Clairfeuille, Thomas
Mas, Caroline
Chan, Audrey S. M.
Yang, Zhe
Tello-Lafoz, Maria
Chandra, Mintu
Wigagdo, Jocelyn
Kerr, Markus
Blessy, Paul
Merida, Isabel
Teasdale, Rohan D.
Pavlos, Nathan J.
Anggono, Victor
Collins, Brett
Title A molecular code for endosomal recycling of phosphorylated cargos by the SNX27–retromer complex
Journal name Nature Structural and Molecular Biology   Check publisher's open access policy
ISSN 1545-9993
Publication date 2016-09-05
Year available 2016
Sub-type Article (original research)
DOI 10.1038/nsmb.3290
Open Access Status Not yet assessed
Volume 23
Issue 10
Start page 921
End page 932
Total pages 14
Place of publication New York, NY United States
Publisher Nature Publishing Group
Language eng
Subject 1315 Structural Biology
1312 Molecular Biology
Abstract Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α5β1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.
Formatted abstract
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 β2 adrenergic
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.
Keyword Biochemistry & Molecular Biology
Cell Biology
Biochemistry & Molecular Biology
Cell Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID DP0985029
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 15 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 30 Sep 2016, 23:16:15 EST by Susan Allen on behalf of Institute for Molecular Bioscience