國家衛生研究院 NHRI:Item 3990099045/5427
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    题名: Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate
    作者: Huang, CH;Suen, CS;Lin, CT;Chien, CH;Lee, HY;Chung, KM;Tsai, TY;Jiaang, WT;Hwang, MJ;Chen, X
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Fibroblast activation protein (FAP) is a prolyl-cleaving endopeptidase proposed as an anticancer drug target. It is necessary to define its cleavage-site specificity to facilitate the identification of its in vivo substrates and to understand its biological functions. We found that the previously identified substrate of FAP, alpha(2)-antiplasmin, is not a robust substrate in vitro. Instead, an intracellular protein, SPRY2, is cleavable by FAP and more suitable for investigation of its substrate specificity in the context of the full-length globular protein. FAP prefers uncharged residues, including small or bulky hydrophobic amino acids, but not charged amino acids, especially acidic residue at P1', P3 and P4 sites. Molecular modeling analysis shows that the substrate binding site of FAP is surrounded by multiple tyrosine residues and some negatively charged residues, which may exert least preference for substrates with acidic residues. This provides an explanation why FAP cannot cleave interleukins, which have a glutamate at either P4 or P2', despite their P3-P2-P1 sites being identical to SPRY2 or alpha-AP. Our study provided new information on FAP cleavage-site specificity, which differs from the data obtained by profiling with a peptide library or with the denatured protein, gelatin, as the substrate. Furthermore, our study suggests that negatively charged residues should be avoided when designing FAP inhibitors.
    日期: 2011-06
    關聯: Journal of Biochemistry. 2011 Jun;149(6):685-692.
    Link to: http://dx.doi.org/10.1093/jb/mvr017
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0021-924X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000291061400007
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=79957846744
    显示于类别:[陳新(2002-2015)] 期刊論文
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