Structural modeling, mutation analysis, and
| Autor: | Dongmei, Yu, Junhuang, Zou, Qian, Chen, Tian, Zhu, Ruifang, Sui, Jun, Yang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
NCBI
National Center for Biotechnology Information FN3 fibronectin III Recombinant protein expression RMSD root mean square deviation TM-score template modeling score I-TASSER Iterative Threading ASSEmbly Refinement Protein folding LGL laminin globular-like RP retinitis pigmentosa Structural model USH Usher syndrome ComputingMethodologies_COMPUTERGRAPHICS LN laminin N-terminal Photoreceptor SMTL SWISS-MODEL template library GMQE global quality estimation score QSQE Quaternary Structure Quality Estimation Cell adhesion LE laminin EGF hFc human Fc fragment Retinitis pigmentosa QMEAN qualitative model energy analysis score mFc mouse Fc fragment Membrane protein LG laminin globular DCC deleted in colorectal cancer Hair cell HGMD Human Gene Mutation Database Usher syndrome Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|