Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB

Zhang，Minghui1; Zhang，Laixing1; Guo，Runyu1; Xiao，Chun1; Yin，Jian1; Zhang，Sensen1; Yang，Maojun1,2

2022-05-05

10.1016/j.str.2022.02.007

STRUCTURE   影响因子和分区

0969-2126

1878-4186

Serine beta-lactamase-like protein (LACTB) is a mammalian mitochondrial serine protease that can specifically hydrolyze peptide bonds adjacent to aspartic acid residues and is structurally related to prokaryotic penicillin-binding proteins. Here, we determined the cryoelectron microscopy structures of human LACTB (hLACTB) filaments from wild-type protein, a middle region deletion mutant, and in complex with the inhibitor Z-AAD-CMK at 3.0-, 3.1-, and 2.8-Å resolution, respectively. Structural analysis and activity assays revealed that three interfaces are required for the assembly of hLACTB filaments and that the formation of higher order helical structures facilitates its cleavage activity. Further structural and enzymatic analyses of middle region deletion constructs indicated that, while this region is necessary for substrate hydrolysis, it is not required for filament formation. Moreover, the inhibitor-bound structure showed that hLACTB may cleave peptide bonds adjacent to aspartic acid residues. These findings provide the structural basis underlying hLACTB catalytic activity.

filament structure human LACTB hydrolysis activity inhibitor binding site

SCI

英语

通讯

National Key Research and Development Program of China[2016YFA0501100];National Key Research and Development Program of China[2017YFA0504600];Tsinghua University[20201080572];National Natural Science Foundation of China[21532004];National Natural Science Foundation of China[32030056];Beijing Municipal Natural Science Foundation[5214024];

Biochemistry & Molecular Biology ; Biophysics ; Cell Biology

Biochemistry & Molecular Biology ; Biophysics ; Cell Biology

WOS:000799220200005

CELL PRESS

BIOLOGY & BIOCHEMISTRY

2-s2.0-85129369366

Scopus

1.Ministry of Education Key Laboratory of Protein Science,Tsinghua-Peking Center for Life Sciences,Beijing Advanced Innovation Center for Structural Biology,School of Life Sciences,Tsinghua University,Beijing,100084,China
2.Cryo-EM Facility Center,Southern University of Science & Technology,Shenzhen,Guangdong,518055,China

Zhang，Minghui,Zhang，Laixing,Guo，Runyu,et al. Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB[J]. STRUCTURE,2022,30(5):685-696.e5.

Zhang，Minghui.,Zhang，Laixing.,Guo，Runyu.,Xiao，Chun.,Yin，Jian.,...&Yang，Maojun.(2022).Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB.STRUCTURE,30(5),685-696.e5.

Zhang，Minghui,et al."Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB".STRUCTURE 30.5(2022):685-696.e5.