Disorder-to-Order Transition of an Active-Site Loop Mediates the Allosteric Activation of Sortase A.
Intrinsically disordered proteins and intrinsically disordered regions are implicated in many biological functions and associated with many diseases, but their conformational characterizations are challenging. The disordered β6/β7 loop of Staphylococcus aureus sortase A is involved in the binding of both sorting signals and calcium. Calcium binding allosterically activates the enzyme, but the detailed mechanism has been unclear. Here we adapted the replica exchange with solute tempering method to sample the conformations of the β6/β7 loop, in apo form and in three liganded forms (bound with a sorting signal or calcium or both). The extensive molecular dynamics simulations yield atomic details of the disordered-to-order transition of the loop and suggest a mechanism for allosteric activation: calcium binding results in partial closure and ordering of the loop, thereby leading to preorganization of the binding pocket for the sorting signal. The approach has general applicability to the study of intrinsically disordered regions.
Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida.
Xiaodong
X
Pang
Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida. Electronic address: hzhou4@fsu.edu.
Huan-Xiang
HX
Zhou
D000494:Allosteric Regulation; D019881:Aminoacyltransferases / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry; D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013211:Staphylococcus aureus
D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases; D002118:Calcium