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Application of directed evolution and back-to-consensus algorithms to human alpha1-antitrypsin leads to diminished anti-protease activity and augmented anti-inflammatory activities.
Cellular Immunology ( IF 4.3 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.cellimm.2020.104135
Yotam Lior 1 , Maria Jasevitch 1 , David E Ochayon 1 , Mariana Zaretsky 2 , Eli C Lewis 1 , Amir Aharoni 2
Affiliation  

Primarily known as an elastase inhibitor, human alpha1-antitrypsin also exerts anti-inflammatory and immunomodulatory effects, both in vitro and in vivo. While the anti-protease mechanism of alpha1-antitrypsin is attributed to a particular protein domain coined the reactive center loop, anti-inflammatory and immunomodulatory loci within the molecule remain to be identified. In the present study, directed evolution and back-to-consensus algorithms were applied to human alpha1-antitrypsin. Six unique functional candidate sites were identified on the surface of the molecule; in manipulating these sites by point mutations, a recombinant mutant form of alpha1-antitrypsin was produced, depicting a requirement for sites outside the reactive center loop as essential for protease inhibition, and displaying enhanced anti-inflammatory activities. Taken together, outcomes of the present study establish a potential use for directed evolution in advancing our understanding of site-specific protein functions, offering a platform for development of context- and disease-specific alpha1-antitrypsin–based therapeutics.



中文翻译:

定向进化和背对共识算法应用于人类alpha1-antitrypsin导致减少的抗蛋白酶活性和增强的抗炎活性。

人α1-抗胰蛋白酶最初被称为弹性蛋白酶抑制剂,在体外和体内也都具有抗炎和免疫调节作用。虽然α1-抗胰蛋白酶的抗蛋白酶机制归因于反应中心环的特殊蛋白质结构域,但分子中的抗炎和免疫调节位点仍有待确定。在本研究中,定向进化和回到共识算法被应用于人类α1-抗胰蛋白酶。在分子表面鉴定出六个独特的功能候选位点;在通过点突变操纵这些位点的过程中,产生了α1-抗胰蛋白酶的重组突变体形式,表明需要活性中心环以外的位点作为蛋白酶抑制所必需,并显示出增强的抗炎活性。

更新日期:2020-05-21
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