4v2e | pdb_00004v2e

FLRT3 LRR domain

Structural highlights

4v2e is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FLRT3_MOUSE Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners (PubMed:19056886, PubMed:25374360). Plays a role in the spatial organization of brain neurons (PubMed:25374360). Plays a role in vascular development in the retina (PubMed:25374360). Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells (PubMed:22405201, PubMed:25374360). Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1 (PubMed:24560577). Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members (PubMed:21673655, PubMed:25374360). Promotes neurite outgrowth (in vitro) (By similarity). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length (By similarity). Plays a role in the regulation of the density of glutamaergic synapses (PubMed:22405201). Plays a role in fibroblast growth factor-mediated signaling cascades (PubMed:16872596). Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning (PubMed:19056886). Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development (PubMed:18448090). Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development (PubMed:19056886).[UniProtKB:B1H234]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

FLRTs are broadly expressed proteins with the unique property of acting as homophilic cell adhesion molecules and as heterophilic repulsive ligands of Unc5/Netrin receptors. How these functions direct cell behavior and the molecular mechanisms involved remain largely unclear. Here we use X-ray crystallography to reveal the distinct structural bases for FLRT-mediated cell adhesion and repulsion in neurons. We apply this knowledge to elucidate FLRT functions during cortical development. We show that FLRTs regulate both the radial migration of pyramidal neurons, as well as their tangential spread. Mechanistically, radial migration is controlled by repulsive FLRT2-Unc5D interactions, while spatial organization in the tangential axis involves adhesive FLRT-FLRT interactions. Further, we show that the fundamental mechanisms of FLRT adhesion and repulsion are conserved between neurons and vascular endothelial cells. Our results reveal FLRTs as powerful guidance factors with structurally encoded repulsive and adhesive surfaces.

FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development.,Seiradake E, del Toro D, Nagel D, Cop F, Hartl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R Neuron. 2014 Oct 22;84(2):370-85. doi: 10.1016/j.neuron.2014.10.008. Epub 2014, Oct 22. PMID:25374360^[8]

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

References

↑ Haines BP, Wheldon LM, Summerbell D, Heath JK, Rigby PW. Regulated expression of FLRT genes implies a functional role in the regulation of FGF signalling during mouse development. Dev Biol. 2006 Sep 1;297(1):14-25. Epub 2006 Apr 21. PMID:16872596 doi:https://dx.doi.org/S0012-1606(06)00282-X
↑ Maretto S, Müller PS, Aricescu AR, Cho KW, Bikoff EK, Robertson EJ. Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3. Dev Biol. 2008 Jun 1;318(1):184-93. PMID:18448090 doi:10.1016/j.ydbio.2008.03.021
↑ Egea J, Erlacher C, Montanez E, Burtscher I, Yamagishi S, Hess M, Hampel F, Sanchez R, Rodriguez-Manzaneque MT, Bösl MR, Fässler R, Lickert H, Klein R. Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation. Genes Dev. 2008 Dec 1;22(23):3349-62. PMID:19056886 doi:10.1101/gad.486708
↑ Yamagishi S, Hampel F, Hata K, Del Toro D, Schwark M, Kvachnina E, Bastmeyer M, Yamashita T, Tarabykin V, Klein R, Egea J. FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J. 2011 Jun 14;30(14):2920-33. doi: 10.1038/emboj.2011.189. PMID:21673655 doi:https://dx.doi.org/10.1038/emboj.2011.189
↑ O'Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S, Yates JR 3rd, Ghosh A. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron. 2012 Mar 8;73(5):903-10. doi: 10.1016/j.neuron.2012.01.018. PMID:22405201 doi:https://dx.doi.org/10.1016/j.neuron.2012.01.018
↑ Leyva-Díaz E, del Toro D, Menal MJ, Cambray S, Susín R, Tessier-Lavigne M, Klein R, Egea J, López-Bendito G. FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons. Curr Biol. 2014 Mar 3;24(5):494-508. PMID:24560577 doi:10.1016/j.cub.2014.01.042
↑ Seiradake E, del Toro D, Nagel D, Cop F, Hartl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R. FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron. 2014 Oct 22;84(2):370-85. doi: 10.1016/j.neuron.2014.10.008. Epub 2014, Oct 22. PMID:25374360 doi:https://dx.doi.org/10.1016/j.neuron.2014.10.008
↑ Seiradake E, del Toro D, Nagel D, Cop F, Hartl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R. FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron. 2014 Oct 22;84(2):370-85. doi: 10.1016/j.neuron.2014.10.008. Epub 2014, Oct 22. PMID:25374360 doi:https://dx.doi.org/10.1016/j.neuron.2014.10.008

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OCA

[1] Haines BP, Wheldon LM, Summerbell D, Heath JK, Rigby PW. Regulated expression of FLRT genes implies a functional role in the regulation of FGF signalling during mouse development. Dev Biol. 2006 Sep 1;297(1):14-25. Epub 2006 Apr 21. PMID:16872596 doi:https://dx.doi.org/S0012-1606(06)00282-X

[2] Maretto S, Müller PS, Aricescu AR, Cho KW, Bikoff EK, Robertson EJ. Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3. Dev Biol. 2008 Jun 1;318(1):184-93. PMID:18448090 doi:10.1016/j.ydbio.2008.03.021

[3] Egea J, Erlacher C, Montanez E, Burtscher I, Yamagishi S, Hess M, Hampel F, Sanchez R, Rodriguez-Manzaneque MT, Bösl MR, Fässler R, Lickert H, Klein R. Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation. Genes Dev. 2008 Dec 1;22(23):3349-62. PMID:19056886 doi:10.1101/gad.486708

[4] Yamagishi S, Hampel F, Hata K, Del Toro D, Schwark M, Kvachnina E, Bastmeyer M, Yamashita T, Tarabykin V, Klein R, Egea J. FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J. 2011 Jun 14;30(14):2920-33. doi: 10.1038/emboj.2011.189. PMID:21673655 doi:https://dx.doi.org/10.1038/emboj.2011.189

[5] O'Sullivan ML, de Wit J, Savas JN, Comoletti D, Otto-Hitt S, Yates JR 3rd, Ghosh A. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron. 2012 Mar 8;73(5):903-10. doi: 10.1016/j.neuron.2012.01.018. PMID:22405201 doi:https://dx.doi.org/10.1016/j.neuron.2012.01.018

[6] Leyva-Díaz E, del Toro D, Menal MJ, Cambray S, Susín R, Tessier-Lavigne M, Klein R, Egea J, López-Bendito G. FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons. Curr Biol. 2014 Mar 3;24(5):494-508. PMID:24560577 doi:10.1016/j.cub.2014.01.042

[7] Seiradake E, del Toro D, Nagel D, Cop F, Hartl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R. FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron. 2014 Oct 22;84(2):370-85. doi: 10.1016/j.neuron.2014.10.008. Epub 2014, Oct 22. PMID:25374360 doi:https://dx.doi.org/10.1016/j.neuron.2014.10.008

[8] Seiradake E, del Toro D, Nagel D, Cop F, Hartl R, Ruff T, Seyit-Bremer G, Harlos K, Border EC, Acker-Palmer A, Jones EY, Klein R. FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron. 2014 Oct 22;84(2):370-85. doi: 10.1016/j.neuron.2014.10.008. Epub 2014, Oct 22. PMID:25374360 doi:https://dx.doi.org/10.1016/j.neuron.2014.10.008

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4v2e | pdb_00004v2e

FLRT3 LRR domain

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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