Cryo-EM structure of the PlexinC1/A39R complex reveals inter-domain interactions critical for ligand-induced activation

Kuo, Yi Chun; Chen, Hua; Shang, Guijun; Uchikawa, E.; Tian, Hui; Bai, Xiao Chen; Zhang, Xuewu

doi:10.1038/s41467-020-15862-0

Cited by 15 publications

(18 citation statements)

References 41 publications

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“…Several purification protocols have been developed that sustain membrane proteins in a native membrane-like environment (16)(17)(18)(19). In this study, we reconstituted Pdr5 in peptidiscs, which are short amphipathic bi-helical peptides (17) compatible with single-particle cryo-EM (20,21), after purification from S. cerevisiae cell membranes. This yielded homogenous particles readily visualised by electron cryo-microscopy ( Fig.…”

Section: Pdr5 Reconstituted In a Detergent-free System Can Be Imaged mentioning

confidence: 99%

Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Harris

Wagner

et al. 2021

Preprint

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Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Through the coupling of nucleotide hydrolysis with drug efflux, Pdr5 homologues enable pathogenic species to survive in the presence of chemically diverse antifungal agents. Our structural and functional results reveal details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens avenues for the development of effective antifungal compounds.

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Section: Pdr5 Reconstituted In a Detergent-free System Can Be Imaged mentioning

confidence: 99%

Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Harris

Wagner

et al. 2021

Preprint

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“…Extensive structural analyses of plexin have led to a general model on how dimeric semaphorin binds and induces the dimerization and activation of plexin 6,7,9,10,13,33,34 . While all the plexins use similar mechanisms of activation, there are some important differences for some plexin family members.…”

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confidence: 99%

“…While all the plexins use similar mechanisms of activation, there are some important differences for some plexin family members. For example, PlexinC1 has a distinct extracellular architecture, and therefore the overall shape of the semaphorin-induced dimer of PlexinC1 appears quite different from that of class A plexins 33 . A crystal structure of the a1 domain of Nrp1 in complex with PlexinA2 and Sema3A shows that the Nrp1-a1 domain stabilizes the complex by binding the Sema domains of both semaphorin and plexin simultaneously 7 .…”

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confidence: 99%

Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex

Shang

et al. 2021

Nat Commun

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Secreted class 3 semaphorins (Sema3s) form tripartite complexes with the plexin receptor and neuropilin coreceptor, which are both transmembrane proteins that together mediate semaphorin signal for neuronal axon guidance and other processes. Despite extensive investigations, the overall architecture of and the molecular interactions in the Sema3/plexin/neuropilin complex are incompletely understood. Here we present the cryo-EM structure of a near intact extracellular region complex of Sema3A, PlexinA4 and Neuropilin 1 (Nrp1) at 3.7 Å resolution. The structure shows a large symmetric 2:2:2 assembly in which each subunit makes multiple interactions with others. The two PlexinA4 molecules in the complex do not interact directly, but their membrane proximal regions are close to each other and poised to promote the formation of the intracellular active dimer for signaling. The structure reveals a previously unknown interface between the a2b1b2 module in Nrp1 and the Sema domain of Sema3A. This interaction places the a2b1b2 module at the top of the complex, far away from the plasma membrane where the transmembrane regions of Nrp1 and PlexinA4 embed. As a result, the region following the a2b1b2 module in Nrp1 must span a large distance to allow the connection to the transmembrane region, suggesting an essential role for the long non-conserved linkers and the MAM domain in neuropilin in the semaphorin/plexin/neuropilin complex.

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“…In what way are the extracellular segment and cytosolic portion of type-I transmembrane proteins coupled to organize adhesion and signaling? Currently, there is no detailed structural data that shows the direct coupling of the extracellular part of the protein with its cytosolic part, although several attempts have been made toward this endeavor (Ge et al, 2018 ; Uchikawa et al, 2019 ; Kuo et al, 2020 ). Most likely the transmembrane connection between the two segments, embedded in micelles or nanodisks confers too much flexibility in this setting, precluding structure solution.…”

Section: Discussionmentioning

confidence: 99%

Structural Perspectives on Extracellular Recognition and Conformational Changes of Several Type-I Transmembrane Receptors

Chataigner

Leloup²,

Janssen

2020

Front. Mol. Biosci.

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Type-I transmembrane proteins represent a large group of 1,412 proteins in humans with a multitude of functions in cells and tissues. They are characterized by an extracellular, or luminal, N-terminus followed by a single transmembrane helix and a cytosolic C-terminus. The domain composition and structures of the extracellular and intercellular segments differ substantially amongst its members. Most of the type-I transmembrane proteins have roles in cell signaling processes, as ligands or receptors, and in cellular adhesion. The extracellular segment often determines specificity and can control signaling and adhesion. Here we focus on recent structural understanding on how the extracellular segments of several diverse type-I transmembrane proteins engage in interactions and can undergo conformational changes for their function. Interactions at the extracellular side by proteins on the same cell or between cells are enhanced by the transmembrane setting. Extracellular conformational domain rearrangement and structural changes within domains alter the properties of the proteins and are used to regulate signaling events. The combination of structural properties and interactions can support the formation of larger-order assemblies on the membrane surface that are important for cellular adhesion and intercellular signaling.

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Cryo-EM structure of the PlexinC1/A39R complex reveals inter-domain interactions critical for ligand-induced activation

Cited by 15 publications

References 41 publications

Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex

Structural Perspectives on Extracellular Recognition and Conformational Changes of Several Type-I Transmembrane Receptors

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