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An internal ligand-bound, metastable state of a leukocyte integrin, ?X?2.

ABSTRACT: How is massive conformational change in integrins achieved on a rapid timescale? We report crystal structures of a metastable, putative transition state of integrin ?X?2. The ?X?2 ectodomain is bent; however, a lattice contact stabilizes its ligand-binding ?I domain in a high affinity, open conformation. Much of the ?I ?7 helix unwinds, loses contact with the ?I domain, and reshapes to form an internal ligand that binds to the interface between the ? propeller and ?I domains. Lift-off of the ?I domain above this platform enables a range of extensional and rotational motions without precedent in allosteric machines. Movements of secondary structure elements in the ?2 ?I domain occur in an order different than in ?3 integrins, showing that integrin ? subunits can be specialized to assume different intermediate states between closed and open. Mutations demonstrate that the structure trapped here is metastable and can enable rapid equilibration between bent and extended-open integrin conformations and up-regulation of leukocyte adhesiveness.

SUBMITTER: Sen M

PROVIDER: S-EPMC3840939 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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An internal ligand-bound, metastable state of a leukocyte integrin, αXβ2.

Sen Mehmet M Yuki Koichi K Springer Timothy A TA

The Journal of cell biology 20131101 4

How is massive conformational change in integrins achieved on a rapid timescale? We report crystal structures of a metastable, putative transition state of integrin αXβ2. The αXβ2 ectodomain is bent; however, a lattice contact stabilizes its ligand-binding αI domain in a high affinity, open conformation. Much of the αI α7 helix unwinds, loses contact with the αI domain, and reshapes to form an internal ligand that binds to the interface between the β propeller and βI domains. Lift-off of the αI ...[more]

PMID: 24385486

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Project description:ATP Binding Cassette (ABC) transporters couple the binding and hydrolysis of ATP to the transport of substrate molecules across the membrane. The mechanism by which ATP binding and/or hydrolysis drives the conformational changes associated with substrate transport has not yet been characterized fully. Here, changes in the conformation of the ABC export protein P-glycoprotein on ATP binding are examined in a series of molecular dynamics simulations. When one molecule of ATP is placed at the ATP binding site associated with each of the two nucleotide binding domains (NBDs), the membrane-embedded P-glycoprotein crystal structure adopts two distinct metastable conformations. In one, each ATP molecule interacts primarily with the Walker A motif of the corresponding NBD. In the other, the ATP molecules interacts with both Walker A motif of one NBD and the Signature motif of the opposite NBD inducing the partial dimerization of the NBDs. This interaction is more extensive in one of the two ATP binding site, leading to an asymmetric structure. The overall conformation of the transmembrane domains is not altered in either of these metastable states, indicating that the conformational changes associated with ATP binding observed in the simulations in the absence of substrate do not lead to the outward-facing conformation and thus would be insufficient in themselves to drive transport. Nevertheless, the metastable intermediate ATP-bound conformations observed are compatible with a wide range of experimental cross-linking data demonstrating the simulations do capture physiologically important conformations. Analysis of the interaction between ATP and its cofactor Mg(2+) with each NBD indicates that the coordination of ATP and Mg(2+) differs between the two NBDs. The role structural asymmetry may play in ATP binding and hydrolysis is discussed. Furthermore, we demonstrate that our results are not heavily influenced by the crystal structure chosen for initiation of the simulations.

Dataset Information

An internal ligand-bound, metastable state of a leukocyte integrin, ?X?2.

Publications

An internal ligand-bound, metastable state of a leukocyte integrin, αXβ2.

Similar Datasets

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