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Title: Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies

Abstract

Olfactomedin (OLF) domains are found within extracellular, multidomain proteins in numerous tissues of multicellular organisms. Even though these proteins have been implicated in human disorders ranging from cancers to attention deficit disorder to glaucoma, little is known about their structure(s) and function(s). Here we biophysically, biochemically, and structurally characterize OLF domains from H. sapiens olfactomedin-1 (npoh-OLF, also called noelin, pancortin, OLFM1, and hOlfA), and M. musculus gliomedin (glio-OLF, also called collomin, collmin, and CRG-L2), and compare them with available structures of myocilin (myoc-OLF) recently reported by us and R. norvegicus glio-OLF and M. musculus latrophilin-3 (lat3-OLF) by others. Although the five-bladed β-propeller architecture remains unchanged, numerous physicochemical characteristics differ among these OLF domains. First, npoh-OLF and glio-OLF exhibit prominent, yet distinct, positive surface charges and copurify with polynucleotides. Second, whereas npoh-OLF and myoc-OLF exhibit thermal stabilities typical of human proteins near 55°C, and most myoc-OLF variants are destabilized and highly prone to aggregation, glio-OLF is nearly 20°C more stable and significantly more resistant to chemical denaturation. Phylogenetically, glio-OLF is most similar to primitive OLFs, and structurally, glio-OLF is missing distinguishing features seen in OLFs such as the disulfide bond formed by N- and C- terminal cysteines, the sequestered Ca2+ ionmore » within the propeller central hydrophilic cavity, and a key loop-stabilizing cation-π interaction on the top face of npoh-OLF and myoc-OLF. While deciphering the explicit biological functions, ligands, and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, we used structural insights gained here to generate a new antibody selective for myoc-OLF over npoh-OLF and glio-OLF as a first step in overcoming the impasse in detailed functional characterization of these biomedically important protein domains.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2]
  1. Georgia Inst. of Technology, Atlanta, GA (United States)
  2. Univ. of Iowa, Iowa City, IA (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health
OSTI Identifier:
1245865
Grant/Contract Number:  
R01EY021205; W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 6; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Protein domains; Crystal structure; Heparin; Binding analysis; Molecular structure; Glaucoma; Thermal stability; Disulfide bonds

Citation Formats

Hill, Shannon E., Donegan, Rebecca K., Nguyen, Elaine, Desai, Tanay M., Lieberman, Raquel L., and Anderson, Michael G. Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies. United States: N. p., 2015. Web. doi:10.1371/journal.pone.0130888.
Hill, Shannon E., Donegan, Rebecca K., Nguyen, Elaine, Desai, Tanay M., Lieberman, Raquel L., & Anderson, Michael G. Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies. United States. https://doi.org/10.1371/journal.pone.0130888
Hill, Shannon E., Donegan, Rebecca K., Nguyen, Elaine, Desai, Tanay M., Lieberman, Raquel L., and Anderson, Michael G. 2015. "Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies". United States. https://doi.org/10.1371/journal.pone.0130888. https://www.osti.gov/servlets/purl/1245865.
@article{osti_1245865,
title = {Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies},
author = {Hill, Shannon E. and Donegan, Rebecca K. and Nguyen, Elaine and Desai, Tanay M. and Lieberman, Raquel L. and Anderson, Michael G.},
abstractNote = {Olfactomedin (OLF) domains are found within extracellular, multidomain proteins in numerous tissues of multicellular organisms. Even though these proteins have been implicated in human disorders ranging from cancers to attention deficit disorder to glaucoma, little is known about their structure(s) and function(s). Here we biophysically, biochemically, and structurally characterize OLF domains from H. sapiens olfactomedin-1 (npoh-OLF, also called noelin, pancortin, OLFM1, and hOlfA), and M. musculus gliomedin (glio-OLF, also called collomin, collmin, and CRG-L2), and compare them with available structures of myocilin (myoc-OLF) recently reported by us and R. norvegicus glio-OLF and M. musculus latrophilin-3 (lat3-OLF) by others. Although the five-bladed β-propeller architecture remains unchanged, numerous physicochemical characteristics differ among these OLF domains. First, npoh-OLF and glio-OLF exhibit prominent, yet distinct, positive surface charges and copurify with polynucleotides. Second, whereas npoh-OLF and myoc-OLF exhibit thermal stabilities typical of human proteins near 55°C, and most myoc-OLF variants are destabilized and highly prone to aggregation, glio-OLF is nearly 20°C more stable and significantly more resistant to chemical denaturation. Phylogenetically, glio-OLF is most similar to primitive OLFs, and structurally, glio-OLF is missing distinguishing features seen in OLFs such as the disulfide bond formed by N- and C- terminal cysteines, the sequestered Ca2+ ion within the propeller central hydrophilic cavity, and a key loop-stabilizing cation-π interaction on the top face of npoh-OLF and myoc-OLF. While deciphering the explicit biological functions, ligands, and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, we used structural insights gained here to generate a new antibody selective for myoc-OLF over npoh-OLF and glio-OLF as a first step in overcoming the impasse in detailed functional characterization of these biomedically important protein domains.},
doi = {10.1371/journal.pone.0130888},
url = {https://www.osti.gov/biblio/1245865}, journal = {PLoS ONE},
issn = {1932-6203},
number = 6,
volume = 10,
place = {United States},
year = {Mon Jun 29 00:00:00 EDT 2015},
month = {Mon Jun 29 00:00:00 EDT 2015}
}

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Works referenced in this record:

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journal, August 2001


Genetic dissection of myocilin glaucoma
journal, January 2004


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Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma
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The Stability of Myocilin Olfactomedin Domain Variants Provides New Insight into Glaucoma as a Protein Misfolding Disorder
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Glaucoma-associated myocilin: A better understanding but much more to learn
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The Glaucoma-Associated Olfactomedin Domain of Myocilin Forms Polymorphic Fibrils That Are Constrained by Partial Unfolding and Peptide Sequence
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Pancortins interact with amyloid precursor protein and modulate cortical cell migration
journal, September 2012


The many blades of the β-propeller proteins: conserved but versatile
journal, October 2011


Increased expression of olfactomedin-1 and myocilin in podocytes during puromycin aminonucleoside nephrosis
journal, June 2010


The Olfactomedin Domain from Gliomedin Is a β-Propeller with Unique Structural Properties
journal, December 2014


Glucose-regulated Protein 94 Triage of Mutant Myocilin through Endoplasmic Reticulum-associated Degradation Subverts a More Efficient Autophagic Clearance Mechanism
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Ligands for Glaucoma-Associated Myocilin Discovered by a Generic Binding Assay
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Secreted gliomedin is a perinodal matrix component of peripheral nerves
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Structural basis for misfolding in myocilin-associated glaucoma
journal, December 2014


Myocilin allele-specific glaucoma phenotype database
journal, February 2008


A genome-wide association meta-analysis identifies new childhood obesity loci
journal, April 2012


Olfactomedin-4 is a glycoprotein secreted into mucus in active IBD
journal, May 2012


Amyloid Fibril Formation by the Glaucoma-Associated Olfactomedin Domain of Myocilin
journal, August 2012


Rescue of Glaucoma-Causing Mutant Myocilin Thermal Stability by Chemical Chaperones
journal, March 2010


Olfactomedin-1 activity identifies a cell invasion checkpoint during epithelial-mesenchymal transition in the chick embryonic heart
journal, December 2012


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journal, July 2007


SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling
journal, January 1997


Myocilin allele-specific glaucoma phenotype database
journal, February 2008


Olfactomedin-4 is a glycoprotein secreted into mucus in active IBD
journal, May 2012


Glaucoma-associated myocilin: A better understanding but much more to learn
journal, April 2009


Amyloid Fibril Formation by the Glaucoma-Associated Olfactomedin Domain of Myocilin
journal, August 2012


The Glaucoma-Associated Olfactomedin Domain of Myocilin Forms Polymorphic Fibrils That Are Constrained by Partial Unfolding and Peptide Sequence
journal, February 2014


MicroRNAs Shape the Neuronal Landscape
journal, August 2012


The many blades of the β-propeller proteins: conserved but versatile
journal, October 2011


Novel Sequences Propel Familiar Folds
journal, April 2002


Characterization and differential expression of a human gene family of olfactomedin-related proteins
journal, August 2000


The Stability of Myocilin Olfactomedin Domain Variants Provides New Insight into Glaucoma as a Protein Misfolding Disorder
journal, July 2011


Ligands for Glaucoma-Associated Myocilin Discovered by a Generic Binding Assay
journal, November 2013


Rescue of Glaucoma-Causing Mutant Myocilin Thermal Stability by Chemical Chaperones
journal, March 2010


Docking Server for the Identification of Heparin Binding Sites on Proteins
journal, July 2014


Noelin-1 is a secreted glycoprotein involved in generation of the neural crest
journal, March 2000


Electrostatics of nanosystems: Application to microtubules and the ribosome
journal, August 2001


The beta bulge: a common small unit of nonrepetitive protein structure.
journal, June 1978


Fibronectin Type III-like Domains of Neurofascin-186 Protein Mediate Gliomedin Binding and Its Clustering at the Developing Nodes of Ranvier
journal, October 2011


Olfactomedin 1 Interacts with the Nogo A Receptor Complex to Regulate Axon Growth
journal, August 2012


Cleavage and Oligomerization of Gliomedin, a Transmembrane Collagen Required for Node of Ranvier Formation
journal, February 2007


A Cellular Assay Distinguishes Normal and Mutant TIGR/Myocilin Protein
journal, November 1999


Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma
journal, July 2014


Structural basis for misfolding in myocilin-associated glaucoma
journal, December 2014


DISPLAR: an accurate method for predicting DNA-binding sites on protein surfaces
journal, February 2007


Characterization of extracellular circulating microRNA
journal, May 2011


Increased expression of olfactomedin-1 and myocilin in podocytes during puromycin aminonucleoside nephrosis
journal, June 2010


Targeted Disruption of the Myocilin Gene (Myoc) Suggests that Human Glaucoma-Causing Mutations Are Gain of Function
journal, November 2001


Pancortins interact with amyloid precursor protein and modulate cortical cell migration
journal, September 2012


Olfactomedin-1 activity identifies a cell invasion checkpoint during epithelial-mesenchymal transition in the chick embryonic heart
journal, December 2012


A genome-wide association meta-analysis identifies new childhood obesity loci
journal, March 2012


Works referencing / citing this record:

Binding of a glaucoma-associated myocilin variant to the αB-crystallin chaperone impedes protein clearance in trabecular meshwork cells
journal, November 2018


Stable calcium-free myocilin olfactomedin domain variants reveal challenges in differentiating between benign and glaucoma-causing mutations
journal, July 2019


Calcium-ligand variants of the myocilin olfactomedin propeller selected from invertebrate phyla reveal cross-talk with N-terminal blade and surface helices
journal, August 2019


Design and structural characterisation of olfactomedin-1 variants as tools for functional studies
journal, November 2019


Automated Structure- and Sequence-Based Design of Proteins for High Bacterial Expression and Stability
journal, April 2018


Design and structural characterisation of olfactomedin-1 variants as tools for functional studies
journal, November 2019