Structural modeling, mutation analysis, and
Cell adhesion
DCC, deleted in colorectal cancer
FN3, fibronectin III
GMQE, global quality estimation score
HGMD, Human Gene Mutation Database
Hair cell
I-TASSER, Iterative Threading ASSEmbly Refinement
LE, laminin EGF
LG, laminin globular
LGL, laminin globular-like
LN, laminin N-terminal
Membrane protein
NCBI, National Center for Biotechnology Information
Photoreceptor
Protein folding
QMEAN, qualitative model energy analysis score
QSQE, Quaternary Structure Quality Estimation
RMSD, root mean square deviation
RP, retinitis pigmentosa
Recombinant protein expression
Retinitis pigmentosa
SMTL, SWISS-MODEL template library
Structural model
TM-score, template modeling score
USH, Usher syndrome
Usher syndrome
hFc, human Fc fragment
mFc, mouse Fc fragment
Journal
Computational and structural biotechnology journal
ISSN: 2001-0370
Titre abrégé: Comput Struct Biotechnol J
Pays: Netherlands
ID NLM: 101585369
Informations de publication
Date de publication:
2020
2020
Historique:
received:
31
03
2020
revised:
26
05
2020
accepted:
28
05
2020
entrez:
9
7
2020
pubmed:
9
7
2020
medline:
9
7
2020
Statut:
epublish
Résumé
Usherin is the most common causative protein associated with autosomal recessive retinitis pigmentosa (RP) and Usher syndrome (USH), which are characterized by retinal degeneration alone and in combination with hearing loss, respectively. Usherin is essential for photoreceptor survival and hair cell bundle integrity. However, the molecular mechanism underlying usherin function in normal and disease conditions is unclear. In this study, we investigated structural models of usherin domains and localization of usherin pathogenic small in-frame mutations, mainly homozygous missense mutations. We found that usherin fibronectin III (FN3) domains and most laminin-related domains have a β-sandwich structure. Some FN3 domains are predicted to interact with each other and with laminin-related domains. The usherin protein may bend at some FN3 linker regions. RP- and USH-associated small in-frame mutations are differentially located in usherin domains. Most of them are located at the periphery of β-sandwiches, with some at the interface between interacting domains. The usherin laminin epidermal growth factor repeats adopt a rod-shaped structure, which is maintained by disulfide bonds. Most missense mutations and deletion of exon 13 in this region disrupt the disulfide bonds and may affect local protein folding. Despite low expression of the recombinant entire protein and protein fragments in mammalian cell culture, usherin FN3 fragments are more robustly expressed and secreted than its laminin-related fragments. Our findings provide new insights into the usherin structure and the disease mechanisms caused by pathogenic small in-frame mutations, which will help inform future experimental research on diagnosis, disease mechanisms, and therapeutic approaches.
Identifiants
pubmed: 32637036
doi: 10.1016/j.csbj.2020.05.025
pii: S2001-0370(20)30288-9
pmc: PMC7317166
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1363-1382Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR002538
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY014800
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY026521
Pays : United States
Organisme : NEI NIH HHS
ID : R21 EY030198
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY020853
Pays : United States
Informations de copyright
© 2020 The Author(s).
Déclaration de conflit d'intérêts
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Références
Int J Biochem Cell Biol. 2014 Jan;46:80-9
pubmed: 24239741
Hum Mutat. 2014 Oct;35(10):1179-86
pubmed: 24944099
J Biol Chem. 2009 Aug 21;284(34):22786-92
pubmed: 19553699
Orphanet J Rare Dis. 2015 Sep 04;10:110
pubmed: 26338283
PLoS One. 2014 Aug 18;9(8):e105439
pubmed: 25133613
Biochim Biophys Acta. 2015 Mar;1852(3):406-20
pubmed: 25481835
Am J Med Genet A. 2015 Jul;167(7):1597-600
pubmed: 25823529
J Med Genet. 2003 Jan;40(1):e8
pubmed: 12525556
Hum Mutat. 2002 Jul;20(1):76-7
pubmed: 12112664
Am J Hum Genet. 2000 Jun;66(6):1975-8
pubmed: 10775529
J Neurosci. 2007 Jun 13;27(24):6478-88
pubmed: 17567809
Mol Genet Genomic Med. 2014 Sep;2(5):393-401
pubmed: 25333064
Mol Biol Evol. 2018 Jun 1;35(6):1547-1549
pubmed: 29722887
Genet Test. 2008 Jun;12(2):289-94
pubmed: 18452394
Sci Rep. 2015 Dec 15;5:18287
pubmed: 26667666
Drug Discov Today. 2009 Oct;14(19-20):949-55
pubmed: 19576999
Invest Ophthalmol Vis Sci. 2014 Oct 16;55(11):7369-75
pubmed: 25324289
Orphanet J Rare Dis. 2011 Oct 17;6:65
pubmed: 22004887
Hum Mutat. 2000 Apr;15(4):388
pubmed: 10738000
Am J Hum Genet. 2000 Apr;66(4):1199-210
pubmed: 10729113
PLoS One. 2014 May 15;9(5):e97808
pubmed: 24831256
Sci Rep. 2017 Sep 11;7(1):11170
pubmed: 28894305
Biochemistry. 2005 Aug 30;44(34):11518-24
pubmed: 16114888
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4413-8
pubmed: 17360538
PLoS Genet. 2010 May 20;6(5):e1000955
pubmed: 20502675
Hear Res. 2015 Feb;320:18-23
pubmed: 25575603
J Med Genet. 2010 Jul;47(7):499-506
pubmed: 20507924
Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):1095-1104
pubmed: 29490346
Nat Protoc. 2010 Apr;5(4):725-38
pubmed: 20360767
Eur J Hum Genet. 2004 May;12(5):407-10
pubmed: 14970843
J Med Genet. 2012 Jan;49(1):27-36
pubmed: 22135276
Genet Med. 2015 Apr;17(4):271-8
pubmed: 25356976
Biophys J. 1998 Jul;75(1):422-7
pubmed: 9649402
Am J Hum Genet. 2004 Apr;74(4):738-44
pubmed: 15015129
J Biol Chem. 2002 Aug 9;277(32):29283-93
pubmed: 12023293
Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1311-7
pubmed: 19683999
Eur J Hum Genet. 2014 Jan;22(1):99-104
pubmed: 23591405
Hear Res. 2016 Sep;339:60-8
pubmed: 27318125
Exp Eye Res. 2018 Aug;173:148-159
pubmed: 29777677
Annu Rev Cell Dev Biol. 2010;26:397-419
pubmed: 20690820
Hum Genet. 2018 Oct;137(10):779-794
pubmed: 30242501
Ophthalmic Genet. 2011 Jun;32(2):65-74
pubmed: 21174530
Hum Mol Genet. 2015 Dec 15;24(24):6944-57
pubmed: 26401052
Hum Mutat. 2007 Aug;28(8):781-9
pubmed: 17405132
Hum Mol Genet. 2014 May 1;23(9):2374-90
pubmed: 24334608
Sci Rep. 2016 Sep 06;6:32792
pubmed: 27596865
Hum Mutat. 2010 Jun;31(6):734-41
pubmed: 20513143
Exp Eye Res. 2001 May;72(5):503-9
pubmed: 11311042
Proteins. 2009;77 Suppl 9:100-13
pubmed: 19768687
Science. 2014 Jun 13;344(6189):1275-9
pubmed: 24876346
Hum Mutat. 2010 Mar;31(3):347-55
pubmed: 20052763
Eur J Hum Genet. 2000 Jul;8(7):500-6
pubmed: 10909849
PLoS One. 2014 Aug 18;9(8):e104281
pubmed: 25133751
Lancet. 2006 Nov 18;368(9549):1795-809
pubmed: 17113430
Ophthalmology. 2016 May;123(5):1151-60
pubmed: 26927203
Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R262-70
pubmed: 16987892
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W252-8
pubmed: 24782522
Hum Mutat. 2004 Aug;24(2):185
pubmed: 15241801
Nucleic Acids Res. 2017 Jan 4;45(D1):D313-D319
pubmed: 27899672
Nucleic Acids Res. 2018 Jul 2;46(W1):W296-W303
pubmed: 29788355
PLoS One. 2015 Sep 09;10(9):e0136561
pubmed: 26352687
Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3699-706
pubmed: 18421091
Biochemistry. 2012 Nov 6;51(44):8814-28
pubmed: 23106217
Hum Mol Genet. 2006 Mar 1;15(5):751-65
pubmed: 16434480
Am J Hum Genet. 2017 Jan 5;100(1):75-90
pubmed: 28041643
Mol Genet Genomic Med. 2014 Jan;2(1):30-43
pubmed: 24498627
Hum Mol Genet. 2020 Jan 30;:
pubmed: 31998945
Mol Biol Evol. 2013 May;30(5):1229-35
pubmed: 23486614
Ophthalmic Genet. 2018 Apr;39(2):291-292
pubmed: 29283788
Sci Rep. 2019 Feb 4;9(1):1219
pubmed: 30718709
Mol Vis. 2011;17:1662-8
pubmed: 21738395
Hum Mutat. 2012 Jan;33(1):104-8
pubmed: 22009552
J Med Genet. 2006 Nov;43(11):e55
pubmed: 17085681
Adv Exp Med Biol. 2019;1185:91-96
pubmed: 31884594
Mol Vis. 2010 Dec 03;16:2550-8
pubmed: 21151602
Mol Vis. 2010 Mar 17;16:454-61
pubmed: 20309401
Eur J Hum Genet. 2015 Oct;23(10):1318-27
pubmed: 25649381
J Cell Sci. 2004 Jan 15;117(Pt 2):233-42
pubmed: 14676276
Exp Eye Res. 2006 Jul;83(1):97-119
pubmed: 16545802
Sci Rep. 2016 Jan 25;6:19531
pubmed: 26806561
PLoS One. 2014 Feb 07;9(2):e88410
pubmed: 24516651
Mol Genet Genomic Med. 2016 Jun 28;4(5):527-539
pubmed: 27957503
Vision Res. 2008 Feb;48(3):433-41
pubmed: 17936325
J Clin Invest. 2011 Feb;121(2):628-39
pubmed: 21266780
Hum Mol Genet. 2012 Feb 1;21(3):692-710
pubmed: 22048959
Exp Eye Res. 2004 Aug;79(2):167-73
pubmed: 15325563