Deciphering the Inter-domain Decoupling in the Gram-negative Bacterial Membrane Insertase

Abstract

YidC is a protein found in membranes that plays an important role in the process of inserting newly generated proteins into lipid membranes. The SecYEG-dependent complex is responsible for inserting proteins into the lipid bilayer, and this process is facilitated by YidC. In addition, YidC acts as a chaperone during the folding processes of proteins. Multiple investigations have conclusively shown that the gram-positive bacterium YidC has SecY-independent insertion mechanisms. Through the use of microsecond level all-atom molecular dynamics simulations, we have carried out the first in-depth investigation of the YidC protein originating from gram-negative bacteria. This research sheds light on the significance of several structural areas related to YidC at an atomic level by utilizing equilibrium molecular dynamics (MD) simulations. In this research, multiple models of YidC inside the lipid bilayer were constructed in order to achieve a deeper understanding of the critical role of the C2 loop and the extra periplasmic domain present in gram-negative YidC. According to the results of our research, the C2 loop is responsible for the overall stabilization of the protein, most notably in the transmembrane region, and it also has an allosteric influence on the periplasmic domain. We have found critical interactions that contribute to the stability of the protein as well as its functional aspect. Finally, our study provides a hypothetical SecY-independent insertion mechanism for gram-negative bacterial YidC.

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

“…There are a number of studies and reviews on how cholesterol modulates class A GPCRs, but this area of study is yet to be fully explored for class C GPCRs. Recent advances in experimental and computational power have enabled researchers to investigate the role of lipids in various membranes and solvable proteins, at the atomic level using molecular dynamics simulation [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

The Alternating Access Mechanism in Mammalian Multidrug Resistance Transporters and Their Bacterial Homologs

“…Electron microscopy and crystallographic studies have revealed the structure of the protein in both the inward- and outward-facing conformations [ 62 , 194 , 195 , 196 ], while Molecular dynamics (MD) simulations have been used to study the alternating access mechanisms [ 43 , 196 , 197 ]. MD is a powerful computational technique used to study the dynamics of biological macromolecules such as proteins [ 198 , 199 ], nucleic acids, and lipids [ 179 , 200 , 201 ]. It is an essential tool for studying the mechanisms of membrane transport proteins [ 106 , 184 , 202 , 203 ], including the alternating access mechanism in Pgp [ 43 , 196 , 197 ].…”

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

“…There are a number of studies and reviews on how cholesterol modulates class A GPCRs, but this area of study is yet to be fully explored for class C GPCRs. Recent advances in experimental and computational power have enabled researchers to investigate the role of lipids in various membranes and solvable proteins, at the atomic level using molecular dynamics simulation [8][9][10][11][12][13].…”

“…The argument for cholesterol addition varies from the stabilization of the protein to aiding dimerization. Experimental analysis and, most recently molecular dynamics simulations [8][9][10][11][12]27] have been used to decipher the possible role of cholesterol in these protein structures. In this review, we will discuss the relevance and position of cholesterol molecules in class C GPCR structures and functions.…”