allosteric regulation
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Author(s):  
Anika L. Burrell ◽  
Chuankai Nie ◽  
Meerit Said ◽  
Jacqueline C. Simonet ◽  
David Fernández-Justel ◽  
...  

2022 ◽  
Vol 119 (2) ◽  
pp. e2102953118
Author(s):  
Varnavas D. Mouchlis ◽  
Daiki Hayashi ◽  
Alexis M. Vasquez ◽  
Jian Cao ◽  
J. Andrew McCammon ◽  
...  

Lipoprotein-associated phospholipase A2 (Lp-PLA2) associates with low- and high-density lipoproteins in human plasma and specifically hydrolyzes circulating oxidized phospholipids involved in oxidative stress. The association of this enzyme with the lipoprotein’s phospholipid monolayer to access its substrate is the most crucial first step in its catalytic cycle. The current study demonstrates unequivocally that a significant movement of a major helical peptide region occurs upon membrane binding, resulting in a large conformational change upon Lp-PLA2 binding to a phospholipid surface. This allosteric regulation of an enzyme’s activity by a large membrane-like interface inducing a conformational change in the catalytic site defines a unique dimension of allosterism. The mechanism by which this enzyme associates with phospholipid interfaces to select and extract a single phospholipid substrate molecule and carry out catalysis is key to understanding its physiological functioning. A lipidomics platform was employed to determine the precise substrate specificity of human recombinant Lp-PLA2 and mutants. This study uniquely elucidates the association mechanism of this enzyme with membranes and its resulting conformational change as well as the extraction and binding of specific oxidized and short acyl-chain phospholipid substrates. Deuterium exchange mass spectrometry coupled with molecular dynamics simulations was used to define the precise specificity of the subsite for the oxidized fatty acid at the sn-2 position of the phospholipid backbone. Despite the existence of several crystal structures of this enzyme cocrystallized with inhibitors, little was understood about Lp-PLA2‘s specificity toward oxidized phospholipids.


Author(s):  
Rojan Shrestha ◽  
Sarah Garrett-Thomson ◽  
Weifeng Liu ◽  
Steven C. Almo ◽  
Andras Fiser

2021 ◽  
Vol 9 (6) ◽  
Author(s):  
Joshua C. Zamora ◽  
Hudson R. Smith ◽  
Elaine M. Jennings ◽  
Teresa S. Chavera ◽  
Varun Kotipalli ◽  
...  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zachary Maben ◽  
Richa Arya ◽  
Dimitris Georgiadis ◽  
Efstratios Stratikos ◽  
Lawrence J. Stern

AbstractThe endoplasmic-reticulum aminopeptidase ERAP1 processes antigenic peptides for loading on MHC-I proteins and recognition by CD8 T cells as they survey the body for infection and malignancy. Crystal structures have revealed ERAP1 in either open or closed conformations, but whether these occur in solution and are involved in catalysis is not clear. Here, we assess ERAP1 conformational states in solution in the presence of substrates, allosteric activators, and inhibitors by small-angle X-ray scattering. We also characterize changes in protein conformation by X-ray crystallography, and we localize alternate C-terminal binding sites by chemical crosslinking. Structural and enzymatic data suggest that the structural reconfigurations of ERAP1 active site are physically linked to domain closure and are promoted by binding of long peptide substrates. These results clarify steps required for ERAP1 catalysis, demonstrate the importance of conformational dynamics within the catalytic cycle, and provide a mechanism for the observed allosteric regulation and Lys/Arg528 polymorphism disease association.


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