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Conformational Flexibility in the Transmembrane Protein TSPO.

ABSTRACT: The translocator protein (TSPO) is an integral membrane protein that interacts with a wide variety of endogenous ligands, such as cholesterol and porphyrins, and is also the target for several small molecules with substantial in vivo efficacy. When complexed with the TSPO-specific radioligand (R)-PK11195, TSPO folds into a rigid five-helix bundle. However, little is known about the structure and dynamics of TSPO in the absence of high-affinity ligands. By means of NMR spectroscopy, we show that TSPO exchanges between multiple conformations in the absence of (R)-PK11195. Extensive motions on time scales from pico- to microseconds occur all along the primary sequence of the protein, leading to a loss of stable tertiary interactions and local unfolding of the helical structure in the vicinity of the ligand-binding site. The flexible nature of TSPO highlights the importance of conformational plasticity in integral membrane proteins.

SUBMITTER: Jaremko L

PROVIDER: S-EPMC5654506 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Conformational Flexibility in the Transmembrane Protein TSPO.

Jaremko Łukasz Ł Jaremko Mariusz M Giller Karin K Becker Stefan S Zweckstetter Markus M

Chemistry (Weinheim an der Bergstrasse, Germany) 20150923 46

The translocator protein (TSPO) is an integral membrane protein that interacts with a wide variety of endogenous ligands, such as cholesterol and porphyrins, and is also the target for several small molecules with substantial in vivo efficacy. When complexed with the TSPO-specific radioligand (R)-PK11195, TSPO folds into a rigid five-helix bundle. However, little is known about the structure and dynamics of TSPO in the absence of high-affinity ligands. By means of NMR spectroscopy, we show that ...[more]

PMID: 26394723

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