2014
DOI: 10.1093/hmg/ddu730
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Structural basis for misfolding in myocilin-associated glaucoma

Abstract: Olfactomedin (OLF) domain-containing proteins play roles in fundamental cellular processes and have been implicated in disorders ranging from glaucoma, cancers and inflammatory bowel disorder, to attention deficit disorder and childhood obesity. We solved crystal structures of the OLF domain of myocilin (myoc-OLF), the best studied such domain to date. Mutations in myoc-OLF are causative in the autosomal dominant inherited form of the prevalent ocular disorder glaucoma. The structures reveal a new addition to … Show more

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Cited by 75 publications
(131 citation statements)
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“…Crystals of the complex were obtained in space group P 4 3 with eight FLRT3/ LPHN3 complexes in the asymmetric unit, and diffracted to d min = 3.6 Å (Table 1). The complex structure was obtained by molecular replacement using the available mouse FLRT3 structure (PDB ID 4V2E) and the mycolin olfactomedin structure (PDB ID 4WXQ, kindly provided by Raquel Lieberman before its release) and was further refined by the recently released human LPHN3 olfactomedin/lectin structure (PDB ID 5AFB) (Donegan et al, 2015; Jackson et al, 2015; Seiradake et al, 2014). …”
Section: Resultsmentioning
confidence: 99%
“…Crystals of the complex were obtained in space group P 4 3 with eight FLRT3/ LPHN3 complexes in the asymmetric unit, and diffracted to d min = 3.6 Å (Table 1). The complex structure was obtained by molecular replacement using the available mouse FLRT3 structure (PDB ID 4V2E) and the mycolin olfactomedin structure (PDB ID 4WXQ, kindly provided by Raquel Lieberman before its release) and was further refined by the recently released human LPHN3 olfactomedin/lectin structure (PDB ID 5AFB) (Donegan et al, 2015; Jackson et al, 2015; Seiradake et al, 2014). …”
Section: Resultsmentioning
confidence: 99%
“…After unsuccessful attempts to express soluble full-length myocilin in E. coli or purify sufficient quantities from spent media of primary human TM cells (not shown), we generated well-behaved constructs of myocilin (Figure 1B, described in detail in STAR Methods) beyond the 30 kDa OLF domain whose structure we solved previously (Donegan et al, 2015). Biophysical characterization of N-terminal domain (NTD) construct NTD 33-226 , which includes three Cys residues and linker regions before and after the predicted CC domain (Figure 1B), reveals the typical circular dichroism (CD) signatures for α-helices.…”
Section: Resultsmentioning
confidence: 99%
“…With the molecular structures of the myocilin CC and OLF domains (Donegan et al, 2015) in hand, we infer that full-length myocilin consists of an N-terminal tetrameric stalk that branches at an obtuse angle into two parallel dimer-of-dimers affixed to paired C-terminal OLF domains. The transition from tetramer to the two dimers begins between Ser69 and Glu112, and most likely includes the lower-CC probability region containing the skip residue, Thr103 (Figure 4A).…”
Section: Discussionmentioning
confidence: 99%
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