Adverse effects of Alport syndrome-related Gly missense mutations on collagen type IV: Insights from molecular simulations and experiments
文献类型: 外文期刊
作者: Yeo, Jingjie 1 ; Qiu, Yimin 1 ; Jung, Gang Seob 2 ; Zhang, Yong-Wei 3 ; Buehler, Markus J. 2 ; Kaplan, David L. 1 ;
作者机构: 1.Tufts Univ, Dept Biomed Engn, 4 Colby St, Medford, MA 02155 USA
2.MIT, LAMM, Dept Civil & Environm Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA
3.ASTAR, Inst High Performance Comp, 1 Fusionopolis Way, Singapore, Singapore
4.Cornell Univ, Sibley Sch Mech & Aerosp Engn, Ithaca, NY 14853 USA
5.Hubei Acad Agr Sci, Natl Biopesticide Engn Technol Res Ctr, Hubei Biopesticide Engn Res Ctr, Biopesticide Branch Hubei Innovat Ctr Agr Sci & T, Wuhan 430064, Peoples R China
关键词: Alport syndrome; Collagen type IV; Molecular dynamics simulation; Experimental assays; Integrin binding; Enzyme digestion; Structural stability
期刊名称:BIOMATERIALS ( 影响因子:12.479; 五年影响因子:12.104 )
ISSN: 0142-9612
年卷期: 2020 年 240 卷
页码:
收录情况: SCI
摘要: Patients with Alport syndrome (AS) exhibit blood and elevated protein levels in their urine, inflamed kidneys, and many other abnormalities. AS is attributed to mutations in type IV collagen genes, particularly glycine missense mutations in the collagenous domain of COL4A5 that disrupt common structural motifs in collagen from the repeat (Gly-Xaa-Yaa)(n )amino acid sequence. To characterize and elucidate the molecular mechanisms underlying how AS-related mutations perturb the structure and function of type IV collagen, experimental studies and molecular simulations were integrated to investigate the structure, stability, protease sensitivity, and integrin binding affinity of collagen-like proteins containing amino acid sequences from the alpha 5(IV) chain and AS-related Gly missense mutations. We show adverse effects where (i) three AS-related Gly missense mutations significantly reduced the structural stability of the collagen in terms of decreased melting temperatures and calorimetric enthalpies, in conjunction with a collective drop in the external work needed to unfold the peptides containing mutation sequences; (ii) due to local unwinding around the sites of mutations, these triple helical peptides were also degraded more rapidly by trypsin and chymotrypsin, as these enzymes could access the collagenous triple helix more easily and increase the number of contacts; (iii) the mutations further abolished the ability of the recombinant collagens to bind to integrins and greatly reduced the binding affinities between collagen and integrins, thus preventing cells from adhering to these mutants. Our unified experimental and computational approach provided underlying insights needed to guide potential therapies for AS that ameliorate the adverse effects from AS disease onset and progression.
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