Paper Report for: Bauer_2020_FEBS.J_287_1035

The alpha/beta-hydrolase fold family is highly diverse in sequence, structure and biochemical function. To investigate the sequence-structure-function relationships, the Lipase Engineering Database (https://led.biocatnet.de) was updated. Overall, 280 638 protein sequences and 1557 protein structures were analysed. All alpha/beta-hydrolases consist of the catalytically active core domain, but they might also contain additional structural modules, resulting in 12 different architectures: core domain only, additional lids at three different positions, three different caps, additional N- or C-terminal domains and combinations of N- and C-terminal domains with caps and lids respectively. In addition, the alpha/beta-hydrolases were distinguished by their oxyanion hole signature (GX-, GGGX- and Y-types). The N-terminal domains show two different folds, the Rossmann fold or the beta-propeller fold. The C-terminal domains show a beta-sandwich fold. The N-terminal beta-propeller domain and the C-terminal beta-sandwich domain are structurally similar to carbohydrate-binding proteins such as lectins. The classification was applied to the newly discovered polyethylene terephthalate (PET)-degrading PETases and MHETases, which are core domain alpha/beta-hydrolases of the GX- and the GGGX-type respectively. To investigate evolutionary relationships, sequence networks were analysed. The degree distribution followed a power law with a scaling exponent gamma = 1.4, indicating a highly inhomogeneous network which consists of a few hubs and a large number of less connected sequences. The hub sequences have many functional neighbours and therefore are expected to be robust toward possible deleterious effects of mutations. The cluster size distribution followed a power law with an extrapolated scaling exponent tau = 2.6, which strongly supports the connectedness of the sequence space of alpha/beta-hydrolases. DATABASE: Supporting data about domains from other proteins with structural similarity to the N- or C-terminal domains of alpha/beta-hydrolases are available in Data Repository of the University of Stuttgart (DaRUS) under doi: https://doi.org/10.18419/darus-458.