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The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway.

ABSTRACT: Cadherins are a large family of calcium-dependent proteins that mediate cellular adherens junction formation and tissue morphogenesis. To date, the most studied cadherins are those classified as classical, which are further divided into type I or type II depending on selected sequence features. Unlike other members of the classical cadherin family, a detailed structural characterization of P-cadherin has not yet been fully obtained. Here, the high-resolution crystal structure determination of the closed form of human P-cadherin EC1-EC2 is reported. The structure shows a novel, monomeric packing arrangement that provides a further snapshot in the yet-to-be-achieved complete description of the highly dynamic cadherin dimerization pathway. Moreover, this is the first multidomain cadherin fragment to be crystallized and structurally characterized in its closed conformation that does not carry any extra N-terminal residues before the naturally occurring aspartic acid at position 1. Finally, two clear alternate conformations are observed for the critical Trp2 residue, suggestive of a transient, metastable state. The P-cadherin structure and packing arrangement shown here provide new and valuable information towards the complete structural characterization of the still largely elusive cadherin dimerization pathway.

SUBMITTER: Dalle Vedove A

PROVIDER: S-EPMC4388168 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway.

Dalle Vedove Andrea A Lucarelli Anna Paola AP Nardone Valentina V Matino Angelica A Parisini Emilio E

Acta crystallographica. Section F, Structural biology communications 20150320 Pt 4

Cadherins are a large family of calcium-dependent proteins that mediate cellular adherens junction formation and tissue morphogenesis. To date, the most studied cadherins are those classified as classical, which are further divided into type I or type II depending on selected sequence features. Unlike other members of the classical cadherin family, a detailed structural characterization of P-cadherin has not yet been fully obtained. Here, the high-resolution crystal structure determination of th ...[more]

PMID: 25849494

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Project description:The thermodynamic reasons why membrane proteins form stable complexes inside the hydrophobic lipid bilayer remain poorly understood. This is largely because of a lack of membrane-protein systems amenable for equilibrium studies and a limited number of methods for measuring these reactions. Recently, we reported the equilibrium dimerization of the CLC-ec1 Cl-/H+ transporter in lipid bilayers (Chadda et al. 2016. eLife https://doi.org/10.7554/eLife.17438), which provided a new type of model system for studying protein association in membranes. The measurement was conducted using the subunit-capture approach, involving passive dilution of the protein in large multilamellar vesicles, followed by single-molecule photobleaching analysis of the Poisson distribution describing protein encapsulation into extruded liposomes. To estimate the fraction of dimers (FDimer ) as a function of protein density, the photobleaching distributions for the nonreactive, ideal monomer and dimer species must be known so that random co-capture probabilities can be accounted for. Previously, this was done by simulating the Poisson process of protein reconstitution into a known size distribution of liposomes composed of Escherichia coli polar lipids (EPLs). In the present study, we investigate the dependency of FDimer and ?G° on the modeling through a comparison of different liposome size distributions (EPL versus 2:1 POPE/POPG). The results show that the estimated FDimer values are comparable, except at higher densities when liposomes become saturated with protein. We then develop empirical controls to directly measure the photobleaching distributions of the nonreactive monomer (CLC-ec1 I201W/I422W) and ideal dimer (WT CLC-ec1 cross-linked by glutaraldehyde or CLC-ec1 R230C/L249C cross-linked by a disulfide bond). The measured equilibrium constants do not depend on the correction method used, indicating the robustness of the subunit-capture approach. This strategy therefore presents a model-free way to quantify protein dimerization in lipid bilayers, offering a simplified strategy in the ongoing effort to characterize equilibrium membrane-protein reactions in membranes.

Dataset Information

The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway.

Publications

The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway.

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