4v2c | pdb_00004v2c

mouse FLRT2 LRR domain in complex with rat Unc5D Ig1 domain

Structural highlights

4v2c is a 4 chain structure with sequence from Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 4Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FLRT2_MOUSE Functions in cell-cell adhesion, cell migration and axon guidance. Mediates cell-cell adhesion via its interactions with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells (PubMed:21350012, PubMed:25728924 PubMed:25374360). May play a role in the migration of cortical neurons during brain development via its interaction with UNC5D (PubMed:21673655). Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5D, and possibly also other UNC-5 family members (PubMed:21673655, PubMed:25728924). Plays a role in fibroblast growth factor-mediated signaling cascades (PubMed:16872596). Required for normal organization of the cardiac basement membrane during embryogenesis, and for normal embryonic epicardium and heart morphogenesis (PubMed:21350012).^[1] ^[2] ^[3] ^[4] ^[5]

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^[6]

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
↑ Muller PS, Schulz R, Maretto S, Costello I, Srinivas S, Bikoff E, Robertson E. The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis. Development. 2011 Apr;138(7):1297-308. doi: 10.1242/dev.059386. Epub 2011 Feb 24. PMID:21350012 doi:https://dx.doi.org/10.1242/dev.059386
↑ 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
↑ 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
↑ Jackson VA, Del Toro D, Carrasquero M, Roversi P, Harlos K, Klein R, Seiradake E. Structural Basis of Latrophilin-FLRT Interaction. Structure. 2015 Feb 17. pii: S0969-2126(15)00037-4. doi:, 10.1016/j.str.2015.01.013. PMID:25728924 doi:https://dx.doi.org/10.1016/j.str.2015.01.013
↑ 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] Muller PS, Schulz R, Maretto S, Costello I, Srinivas S, Bikoff E, Robertson E. The fibronectin leucine-rich repeat transmembrane protein Flrt2 is required in the epicardium to promote heart morphogenesis. Development. 2011 Apr;138(7):1297-308. doi: 10.1242/dev.059386. Epub 2011 Feb 24. PMID:21350012 doi:https://dx.doi.org/10.1242/dev.059386

[3] 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

[4] 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

[5] Jackson VA, Del Toro D, Carrasquero M, Roversi P, Harlos K, Klein R, Seiradake E. Structural Basis of Latrophilin-FLRT Interaction. Structure. 2015 Feb 17. pii: S0969-2126(15)00037-4. doi:, 10.1016/j.str.2015.01.013. PMID:25728924 doi:https://dx.doi.org/10.1016/j.str.2015.01.013

[6] 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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4v2c | pdb_00004v2c

mouse FLRT2 LRR domain in complex with rat Unc5D Ig1 domain

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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