2mxc

Solution structure of the full length sorting nexin 3Solution structure of the full length sorting nexin 3

Structural highlights

2mxc is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SNX3_HUMAN MMEP syndrome. The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving SNX3 has been found in patients with syndromic microphthalmia. Translocation t(6;13)(q21;q12).

Function

SNX3_HUMAN Phosphoinositide-binding protein required for multivesicular body formation. Specifically binds phosphatidylinositol 3-phosphate (PtdIns(P3)). Plays a role in protein transport between cellular compartments. Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G (By similarity). Not involved in EGFR degradation.^[1] ^[2]

Publication Abstract from PubMed

Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This "PIP-stop" releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces.

Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting.,Lenoir M, Ustunel C, Rajesh S, Kaur J, Moreau D, Gruenberg J, Overduin M Nat Commun. 2018 Mar 8;9(1):993. doi: 10.1038/s41467-018-03370-1. PMID:29520003^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Xu Y, Hortsman H, Seet L, Wong SH, Hong W. SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat Cell Biol. 2001 Jul;3(7):658-66. PMID:11433298 doi:http://dx.doi.org/10.1038/35083051
↑ Pons V, Luyet PP, Morel E, Abrami L, van der Goot FG, Parton RG, Gruenberg J. Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies. PLoS Biol. 2008 Sep 2;6(9):e214. doi: 10.1371/journal.pbio.0060214. PMID:18767904 doi:http://dx.doi.org/10.1371/journal.pbio.0060214
↑ Lenoir M, Ustunel C, Rajesh S, Kaur J, Moreau D, Gruenberg J, Overduin M. Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting. Nat Commun. 2018 Mar 8;9(1):993. doi: 10.1038/s41467-018-03370-1. PMID:29520003 doi:http://dx.doi.org/10.1038/s41467-018-03370-1

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OCA

[1] Xu Y, Hortsman H, Seet L, Wong SH, Hong W. SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat Cell Biol. 2001 Jul;3(7):658-66. PMID:11433298 doi:http://dx.doi.org/10.1038/35083051

[2] Pons V, Luyet PP, Morel E, Abrami L, van der Goot FG, Parton RG, Gruenberg J. Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies. PLoS Biol. 2008 Sep 2;6(9):e214. doi: 10.1371/journal.pbio.0060214. PMID:18767904 doi:http://dx.doi.org/10.1371/journal.pbio.0060214

[3] Lenoir M, Ustunel C, Rajesh S, Kaur J, Moreau D, Gruenberg J, Overduin M. Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting. Nat Commun. 2018 Mar 8;9(1):993. doi: 10.1038/s41467-018-03370-1. PMID:29520003 doi:http://dx.doi.org/10.1038/s41467-018-03370-1

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