Dataset Information

Disorder in cholesterol-binding functionality of CRAC peptides: a molecular dynamics study.

ABSTRACT: The cholesterol recognition/interaction amino acid consensus (CRAC) motif is a primary structure pattern used to identify regions that may be responsible for preferential cholesterol binding in many proteins. The leukotoxin LtxA, which is produced by a pathogenic bacterium, contains two CRAC seqences, only one of which is responsible for cholesterol binding, and the binding is required for cytotoxicity. The factors, in addition to the CRAC definition, that may be responsible for cholesterol-binding functionality and atomistic interactions between the CRAC region and cholesterol are as yet unknown. This study uses molecular dynamics simulations to identify structural characteristics and specific interactions of the two LtxA CRAC peptides with both pure phospholipid and binary cholesterol-phospholipid bilayers. We have identified changes in the secondary structure of these peptides that occur upon cholesterol binding, which are not seen when it is associated with a cholesterol-devoid membrane, and which show salient coupling of structural disorder and function. Additionally, the central tyrosine residue of the CRAC motif was found to play a significant role in cholesterol binding, though residues outside of the CRAC motif also influence membrane interactions and functionality of the CRAC region.

SUBMITTER: Miller CM

PROVIDER: S-EPMC4242004 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Disorder in cholesterol-binding functionality of CRAC peptides: a molecular dynamics study.

Miller Cayla M CM Brown Angela C AC Mittal Jeetain J

The journal of physical chemistry. B 20141110 46

The cholesterol recognition/interaction amino acid consensus (CRAC) motif is a primary structure pattern used to identify regions that may be responsible for preferential cholesterol binding in many proteins. The leukotoxin LtxA, which is produced by a pathogenic bacterium, contains two CRAC seqences, only one of which is responsible for cholesterol binding, and the binding is required for cytotoxicity. The factors, in addition to the CRAC definition, that may be responsible for cholesterol-bind ...[more]

PMID: 25347282

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Project description:The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol-binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N-terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C-terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150-X-Y152-X(3)-R156 and R135-X(2)-Y138-X(2)-L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC-resembling motif that we observed in TM I (residues L17-X(2)-F20-X(3)-R24) and to CRAC in TM V. We expect that the CRAC-like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

Dataset Information

Disorder in cholesterol-binding functionality of CRAC peptides: a molecular dynamics study.

Publications

Disorder in cholesterol-binding functionality of CRAC peptides: a molecular dynamics study.

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