April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Crystal structure of the olfactomedin domain of myocilin
Author Affiliations & Notes
  • Raquel L Lieberman
    School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA
  • Rebecca Donegan
    School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA
  • Footnotes
    Commercial Relationships Raquel Lieberman, None; Rebecca Donegan, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5031. doi:
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      Raquel L Lieberman, Rebecca Donegan; Crystal structure of the olfactomedin domain of myocilin. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5031.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

Non-synonymous lesions in the myocilin olfactomedin (OLF) domain comprise the strongest genetic association with early-onset inherited forms of glaucoma, and overexpression of wild-type myocilin is linked to steroid-induced glaucoma. More broadly, OLF domains are found throughout multicellular organisms where they are implicated in cancers and inflammation. In spite of their broad biomedical importance, comprehension of the function of olfactomedins has been hampered by a lack of structural knowledge. The purpose of the study was to crystallize and solve the first X-ray crystallographic structure of an OLF domain.

 
Methods
 

Expression and purification of wild-type OLF domain of myocilin, crystallization of the OLF domain, preparation of derivatives for experimental phasing, synchrotron X-ray data collection, model building and refinement.

 
Results
 

The de novo crystal structure of OLF was solved to 1.9 Å resolution, revealing the molecular architecture and precise location of every amino acid in the domain, as well as surface charges, hydrophilic channels, calcium, and other ions. Hot spots for ligand binding or protein interactions were identified on the surface of the OLF molecule.

 
Conclusions
 

The structure provides residue-specific insights into the effects of glaucoma variants on protein stability and corresponding amyloid propensity. Structural bioinformatics provide critical inferences into the function of myocilin and the large OLF superfamily.

 
Keywords: 659 protein structure/function • 660 proteins encoded by disease genes • 439 calcium  
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