Protein dissection and shuffling for generating recombined proteins

BIOT 31

Yong Chen, zhanglinlin@mail.tsinghua.edu.cn, Tingjian Chen, Hui Hua, and Zhanglin Lin, zhanglinlin@mail.tsinghua.edu.cn. Department of Chemical Engineering, Tsinghua University, 1 Tsinghua Yuan Road, Beijing, China
We have developed a simple method that allows for the facile recombination of distantly related proteins at multiple discrete sites. The approach relies on protein random dissection to search for possible breakage points, which involves the use of a folding reporter to identify soluble shorter peptides independently of protein function. These dissection points are then used as candidate sites for protein recombination. To evaluate this method, two variants of aminoglycoside-3'-phosphotransferase (APHI and APHII) were chosen as model proteins, which share 31.4% amino acid identity. APH I and APH II were recombined at three sites, the library of 16 (24) chimeras was screened, among which 3/16 were found to show resistance to kanamycin, albeit at lower levels compared with the wild-type APH. We further applied random mutation to improve the activity of these chimeras. This protein shuffling method should be useful for creating artificial biocatalysts with sequences from different templates.