Olfactomedin-1 Has a V-shaped Disulfide-linked Tetrameric Structure

Bos, Trusanne G. A. A.; Sharp, Thomas H.; Thies‐Weesie, Dominique M. E.; Janssen, B.J.C.

doi:10.1074/jbc.m115.653485

Cited by 17 publications

(45 citation statements)

References 42 publications

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“…Our LPHN3-OLF structure is very similar to several other OLF domain structures recently determined from LPHN3 (the mouse LPHN3 lectin and olfactomedin-like domains (LPHN3-RBL/OLF)) (Jackson et al, 2015), gliomedin (gliomedin-OLF) (Han and Kursula, 2015), myocilin (myocilin-OLF) (Donegan et al, 2014) and noelin (noelin-OLF) (Pronker et al, 2015) (Table S2, related to Figure 2). Consistently, our LPHN3-OLF structure displays a five-bladed β-propeller folding, i.e.…”

Section: Resultssupporting

confidence: 83%

“…The fact that Phe415 and the proximal Leu414 are involved in a core-buried hydrophobic cluster suggests that the entire loop is less dynamic. In general, solvent accessibility of the OLF β-propeller central cavity appears to be a shared feature as exhibited by the presence of a high density of bound water molecules in the available structures of OLF domains (Donegan et al, 2014; Han and Kursula, 2015; Jackson et al, 2015, Pronker et al, 2015, and this study). Furthermore, most of the Ca 2+ -binding residues in LPHN3-OLF are conserved – or conservatively substituted – in the OLF family, in particular those having their side chain involved in the ion coordination.…”

Section: Discussionmentioning

confidence: 62%

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Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Ranaivoson

Martini

et al. 2015

Structure

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SUMMARY Latrophilins (LPHNs) are adhesion-like G protein coupled receptors implicated in attention-deficit/hyperactivity disorder (ADHD). Recently, LPHN3 was found to regulate excitatory synapse number through trans interactions with fibronectin leucine-rich repeat transmembrane 3 (FLRT3). By isothermal titration calorimetry, we determined that only the olfactomedin (OLF) domain of LPHN3 is necessary for FLRT3 association. By multi-crystal native-SAD phasing, we determined the crystal structure of the OLF domain. This structure is a five-bladed β-propeller with a Ca2+ ion bound in the central pore, which is capped by a mobile loop that allows the ion to exchange with the solvent. The crystal structure of the OLF/FLRT3 complex shows that LPHN3-OLF in the closed state binds with high affinity to the concave face of FLRT3-LRR with a combination of hydrophobic and charged residues. Our study provides structural and functional insights into the molecular mechanism underlying the LPHN3/FLRT3 contribution to the development of glutamatergic synapses.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 62%

Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Ranaivoson

Martini

et al. 2015

Structure

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“…The angle of the V of olfactomedin-1 appears acute, not obtuse like measured for CC 69-185 . In addition, the C-terminal region of the olfactomedin-1 CC, which harbors a disulfide-forming Cys found within the CC (Pronker et al, 2015), is not aligned with the CC-capping residue Cys 185 in myocilin (Figures 4B and S1B). In olfactomedin-1, the end of the disulfide-harboring CC is immediately adjacent to the start of the OLF domain (Pronker et al, 2015) whereas Cys185 in myocilin is remote from the start of the structural OLF near Cys245.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the C-terminal region of the olfactomedin-1 CC, which harbors a disulfide-forming Cys found within the CC (Pronker et al, 2015), is not aligned with the CC-capping residue Cys 185 in myocilin (Figures 4B and S1B). In olfactomedin-1, the end of the disulfide-harboring CC is immediately adjacent to the start of the OLF domain (Pronker et al, 2015) whereas Cys185 in myocilin is remote from the start of the structural OLF near Cys245. Whether the remaining three CC-containing olfactomedin subfamilies adopt a dimer-of-dimers and to what extent they are similar to myocilin or olfactomedin-1, remains to be seen.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, bioinformatics programs detect CCs in olfactomedins, but vary in predictions for register, stoichiometry, and orientation. Olfactomedin-1 (subfamily 1) is the only CC-containing olfactomedin for which a supramolecular organization has been structurally characterized: an apparent V-shaped molecule seen by transmission electron microscopic imaging and small angle X-ray scattering (SAXS) envelope of the full-length protein (Pronker et al, 2015). However, because olfactomedin family CC domains share very low sequence similarity (< 15% overall, ~22% pairwise identity, Figure S1), results from olfactomedin-1 are not predictive of other olfactomedin family members.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin

et al. 2017

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Summary Glaucoma-associated myocilin is a member of the olfactomedins, a protein family involved in neuronal development and human diseases. Molecular studies of the myocilin N-terminal coiled-coils demonstrate a unique tripartite architecture: a Y-shaped parallel dimer-of-dimers with distinct tetramer and dimer regions. The structure of the C-terminal 7-heptad repeat dimer elucidates an unexpected repeat pattern involving inter-strand stabilization by oppositely charged residues. Molecular dynamics simulations reveal an alternate accessible conformation in which the terminal inter-strand disulfide limits the extent of unfolding and results in a kinked configuration. By inference, full-length myocilin is also branched, with two pairs of C-terminal olfactomedin domains. Selected variants within the N-terminal region alter the apparent quaternary structure of myocilin but do so without compromising stability or causing aggregation. In addition to increasing our structural knowledge of naturally-occurring extracellular coiled-coils and biomedically-important olfactomedins, this work broadens the scope of protein misfolding in the pathogenesis of myocilin-associated glaucoma.

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Mutated olfactomedin 1 in the interphotoreceptor matrix of the mouse retina causes functional deficits and vulnerability to light damage

Koch

Rosenhammer

Paper

et al. 2016

Histochem Cell Biol

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Olfactomedin 1 (OLFM1) is a secreted glycoprotein and member of the olfactomedin protein family, which is preferentially expressed in various areas throughout the central nervous system. To learn about the functional properties of OLFM1 in the eye, we investigated its localization in the mouse and pig eye. In addition, we analyzed the ocular phenotype of Olfm1 mutant mice in which 52 amino acids were deleted in the central part (M2 region) of OLFM1. OLFM1 was detected in cornea, sclera, retina, and optic nerve of both wild-type and Olfm1 mutant littermates. By immunohistochemistry and double labeling with the lectin peanut agglutinin, OLFM1 was found in the interphotoreceptor matrix (IPM) of mouse and pig retina where it was directly localized to the inner segments of photoreceptors. Western blotting confirmed the presence of the OLFM1 isoforms pancortin 1 (BMY) and pancortin 2 (BMZ) in the IPM. The retinal phenotype of Olfm1 mutant mice did not obviously differ from that of wild-type littermates. In addition, outer nuclear layer (ONL) and total retinal thickness were not different, and the same was true for the area of the optic nerve in cross sections. Functional changes were observed though by electroretinography, which showed significantly lower a- and b-wave amplitudes in Olfm1 mutant mice when compared to age-matched wild-type mice. When light damage experiments were performed as an experimental paradigm of photoreceptor apoptosis, significantly more TUNEL-positive cells were observed in Olfm1 mutant mice 30 h after light exposure. One week after light exposure, the ONL was significantly thinner in Olfm1 mutant mice than in wild-type littermates indicating increased photoreceptor loss. No differences were observed when rhodopsin turnover or ERK1/2 signaling was investigated. We conclude that OLFM1 is a newly identified IPM molecule that serves an important role for photoreceptor homeostasis, which is significantly compromised in the eyes of Olfm1 mutant mice.

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Olfactomedin-1 Has a V-shaped Disulfide-linked Tetrameric Structure

Cited by 17 publications

References 42 publications

Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Structural and Mechanistic Insights into the Latrophilin3-FLRT3 Complex that Mediates Glutamatergic Synapse Development

Structure and Misfolding of the Flexible Tripartite Coiled-Coil Domain of Glaucoma-Associated Myocilin

Mutated olfactomedin 1 in the interphotoreceptor matrix of the mouse retina causes functional deficits and vulnerability to light damage

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