4tkn

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Structure of the SNX17 FERM domain bound to the second NPxF motif of KRIT1

Structural highlights

4tkn is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SNX17_HUMAN Critical regulator of endosomal recycling of numerous receptors, channels, and other transmembrane proteins. Binds to NPxY sequences in the cytoplasmic tails of target cargos. Plays a role in the sorting of endocytosed LRP1 and APP, and prevents their degradation. Required for maintenance of normal cell surface levels of APP and LRP1. Recycles internalized integrins ITGB1, ITGB5 and their associated alpha subunits, preventing them from lysosomal degradation. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)).[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

Sorting nexin 17 (SNX17) is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. SNX17 localizes to early endosomes where it directly binds NPxY/F motifs in the cytoplasmic tails of its target receptors to mediate their rates of endocytic internalization, recycling, and/or degradation. SNX17 has also been implicated in mediating cell signaling and can interact with cytoplasmic proteins. Krev interaction trapped 1 (KRIT1), a cytoplasmic adaptor protein associated with cerebral cavernous malformations (CCM), has previously been shown to interact with SNX17. Here, we demonstrate that SNX17 indeed binds directly to KRIT1 and map the binding to the second Asn-Pro-x-Tyr/Phe (NPxY/F) motif in KRIT1. We further characterize the interaction as being mediated by the FERM domain of SNX17. We present the co-crystal structure of SNX17-FERM with the KRIT1-NPxF2 peptide to 3.0 A resolution, and demonstrate that the interaction is highly similar in structure and binding affinity to that between SNX17 and p-selectin. We verify the molecular details of the interaction by site directed mutagenesis and pull down assay, and thereby confirm that the major binding site for SNX17 is confined to the NPxF2 motif in KRIT1. Taken together, our results verify a direct interaction between SNX17 and KRIT1 and classify KRIT1 as a SNX17 binding partner.

Structural determinants for binding of Sorting Nexin 17 (SNX17) to the cytoplasmic adaptor protein Krev Interaction Trapped 1 (KRIT1)*,Stiegler AL, Zhang R, Liu W, Boggon TJ J Biol Chem. 2014 Jul 24. pii: jbc.M114.584011. PMID:25059659[7]

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

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See Also

References

  1. ↑ Williams R, Schluter T, Roberts MS, Knauth P, Bohnensack R, Cutler DF. Sorting nexin 17 accelerates internalization yet retards degradation of P-selectin. Mol Biol Cell. 2004 Jul;15(7):3095-105. Epub 2004 Apr 30. PMID:15121882 doi:10.1091/mbc.E04-02-0143
  2. ↑ Knauth P, Schluter T, Czubayko M, Kirsch C, Florian V, Schreckenberger S, Hahn H, Bohnensack R. Functions of sorting nexin 17 domains and recognition motif for P-selectin trafficking. J Mol Biol. 2005 Apr 8;347(4):813-25. PMID:15769472 doi:S0022-2836(05)00144-0
  3. ↑ Czubayko M, Knauth P, Schluter T, Florian V, Bohnensack R. Sorting nexin 17, a non-self-assembling and a PtdIns(3)P high class affinity protein, interacts with the cerebral cavernous malformation related protein KRIT1. Biochem Biophys Res Commun. 2006 Jul 7;345(3):1264-72. Epub 2006 May 2. PMID:16712798 doi:10.1016/j.bbrc.2006.04.129
  4. ↑ Donoso M, Cancino J, Lee J, van Kerkhof P, Retamal C, Bu G, Gonzalez A, Caceres A, Marzolo MP. Polarized traffic of LRP1 involves AP1B and SNX17 operating on Y-dependent sorting motifs in different pathways. Mol Biol Cell. 2009 Jan;20(1):481-97. doi: 10.1091/mbc.E08-08-0805. Epub 2008 Nov, 12. PMID:19005208 doi:10.1091/mbc.E08-08-0805
  5. ↑ Steinberg F, Heesom KJ, Bass MD, Cullen PJ. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J Cell Biol. 2012 Apr 16;197(2):219-30. doi: 10.1083/jcb.201111121. Epub 2012 Apr, 9. PMID:22492727 doi:10.1083/jcb.201111121
  6. ↑ Ghai R, Mobli M, Norwood SJ, Bugarcic A, Teasdale RD, King GF, Collins BM. Phox homology band 4.1/ezrin/radixin/moesin-like proteins function as molecular scaffolds that interact with cargo receptors and Ras GTPases. Proc Natl Acad Sci U S A. 2011 Apr 21. PMID:21512128 doi:10.1073/pnas.1017110108
  7. ↑ Stiegler AL, Zhang R, Liu W, Boggon TJ. Structural determinants for binding of Sorting Nexin 17 (SNX17) to the cytoplasmic adaptor protein Krev Interaction Trapped 1 (KRIT1)* J Biol Chem. 2014 Jul 24. pii: jbc.M114.584011. PMID:25059659 doi:http://dx.doi.org/10.1074/jbc.M114.584011

Contents


PDB ID 4tkn

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