Abstract:YidC is a membrane protein that facilitates the insertion of newly synthesized proteins into lipid membranes. Through YidC, proteins are inserted into the lipid bilayer via the SecYEG-dependent complex. Additionally, YidC functions as a chaperone in protein folding processes. Several studies have provided evidence of its independent insertion mechanism. However, the mechanistic details of the YidC SecY-independent protein insertion mechanism remain elusive at the molecular level. This study elucidates the inse… Show more
“…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 ].…”
Section: Introductionmentioning
confidence: 99%
“…The argument for cholesterol addition varies from stabilizing the protein to aiding dimerization. Experimental analysis and, most recently, molecular dynamics simulations [ 16 , 17 , 61 , 62 , 63 , 64 ] 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.…”
G-protein coupled receptors (GPCRs), one of the largest superfamilies of cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled receptors operate in membranes rich in cholesterol, with an imbalance in cholesterol level within the vicinity of GPCR transmembrane domains affecting the structure and/or function of many GPCRs, a phenomenon that has been linked to several diseases. These effects of cholesterol could result in indirect changes by altering the mechanical properties of the lipid environment or direct changes by binding to specific sites on the protein. There are a number of studies and reviews on how cholesterol modulates class A GPCRs; however, this area of study is yet to be explored for class C GPCRs, which are characterized by a large extracellular region and often form constitutive dimers. This review highlights specific sites of interaction, functions, and structural dynamics involved in the cholesterol recognition of the class C GPCRs. We summarize recent data from some typical family members to explain the effects of membrane cholesterol on the structural features and functions of class C GPCRs and speculate on their corresponding therapeutic potential.
“…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 ].…”
Section: Introductionmentioning
confidence: 99%
“…The argument for cholesterol addition varies from stabilizing the protein to aiding dimerization. Experimental analysis and, most recently, molecular dynamics simulations [ 16 , 17 , 61 , 62 , 63 , 64 ] 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.…”
G-protein coupled receptors (GPCRs), one of the largest superfamilies of cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled receptors operate in membranes rich in cholesterol, with an imbalance in cholesterol level within the vicinity of GPCR transmembrane domains affecting the structure and/or function of many GPCRs, a phenomenon that has been linked to several diseases. These effects of cholesterol could result in indirect changes by altering the mechanical properties of the lipid environment or direct changes by binding to specific sites on the protein. There are a number of studies and reviews on how cholesterol modulates class A GPCRs; however, this area of study is yet to be explored for class C GPCRs, which are characterized by a large extracellular region and often form constitutive dimers. This review highlights specific sites of interaction, functions, and structural dynamics involved in the cholesterol recognition of the class C GPCRs. We summarize recent data from some typical family members to explain the effects of membrane cholesterol on the structural features and functions of class C GPCRs and speculate on their corresponding therapeutic potential.
“…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].…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
G-protein coupled receptors (GPCRs), one of the largest superfamilies of cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled receptors operate in membranes rich in cholesterol, with an imbalance in cholesterol level within the vicinity of GPCR transmembrane domains affecting the structure and/or function of many GPCRs, a phenomenon that has been linked to several diseases. These effects of cholesterol could result in indirect changes by altering the mechanical properties of the lipid environment or direct changes by binding to specific sites on the protein. There are a number of studies and reviews on how cholesterol modulates class A GPCRs, however, this area of study is yet to be explored for class C GPCRs, which are characterized by a large extracellular region and often form constitutive dimers. This review highlights specific sites of interaction, functions, and structural dynamics involved in the cholesterol recognition of the class C GPCRs. We summarize recent data from some typical family members to explain the effects of membrane cholesterol on the structural features and functions of Class C GPCRs and speculate on their corresponding therapeutic potential.
“…YidC is hypothesized to facilitate membrane insertion in both gram-negative and grampositive bacteria by binding incoming peptides through cytoplasmic loop interactions, hydrophobic force, and groove interactions 16,20,47,48 . The hydrophilic groove inside the membrane core of YidC increases the rate of accepting the hydrophilic moieties of a substrate into the membrane 49–52 .…”
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.
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