Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration

He, Huawei; Yang, Taehong; Terman, Jonathan R.; Zhang, Xuewu

doi:10.1073/pnas.0906923106

Cited by 78 publications

(125 citation statements)

References 37 publications

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“…S1). The structure of PlexinB2 cyto , except for the disordered JM-segment, is similar to reported structures of other plexins (2,3,(8)(9)(10). The PDZ domain here is similar to the NMR structure of the PDZ domain of LARG (Fig.…”

Section: Resultssupporting

confidence: 65%

“…Binding of semaphorin to the extracellular region of plexin induces formation of the active dimer of the cytoplasmic region, which transduces signal to downstream pathways (2)(3)(4)(5)(6)(7). The plexin cytoplasmic region contains a juxtamembrane segment (JM-segment), a RhoGTPase binding domain (RBD), and a GTPase activating protein (GAP) domain (8)(9)(10). The GAP domain, activated by the dimerization, transduces signal through converting its substrate GTPase Rap from the GTP-bound active to the GDP-bound inactive state (2,3).…”

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confidence: 99%

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Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ–RhoGEF

Pascoe

Gutowski

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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PDZ domains are abundant protein interaction modules and typically recognize a short motif at the C terminus of their ligands, with a few residues in the motif endowing the binding specificity. The sequence-based rules, however, cannot fully account for the specificity between the vast number of PDZ domains and ligands in the cell. Plexins are transmembrane receptors that regulate processes such as axon guidance and angiogenesis. Two related guanine nucleotide exchange factors (GEFs), PDZ-RhoGEF and leukemiaassociated RhoGEF (LARG), use their PDZ domains to bind class B plexins and play critical roles in signaling. Here, we present the crystal structure of the full-length cytoplasmic region of PlexinB2 in complex with the PDZ domain of PDZ-RhoGEF. The structure reveals that, in addition to the canonical C-terminal motif/PDZ interaction, the 3D domain of PlexinB2 forms a secondary interface with the PDZ domain. Our biophysical and cell-based assays show that the secondary interface contributes to the specific interaction between plexin and PDZ-RhoGEF and to signaling by plexin in the cell. Formation of secondary interfaces may be a general mechanism for increasing affinity and specificity of modular domain-mediated interactions.PDZ | plexin | signaling | protein interaction module | specificity P lexins are cell surface receptors for semaphorins, extracellular cues that control essential processes such as neuronal axon guidance and vasculature development (1). Binding of semaphorin to the extracellular region of plexin induces formation of the active dimer of the cytoplasmic region, which transduces signal to downstream pathways (2-7). The plexin cytoplasmic region contains a juxtamembrane segment (JM-segment), a RhoGTPase binding domain (RBD), and a GTPase activating protein (GAP) domain (8-10). The GAP domain, activated by the dimerization, transduces signal through converting its substrate GTPase Rap from the GTP-bound active to the GDP-bound inactive state (2, 3). The RBD regulates plexin activity in response to binding of Rho family GTPases, such as Rac1 (reviewed in ref. 11).In addition to the common signaling pathways through the domains shared by all plexins, class B plexins (B1, B2, and B3) mediate a pathway through their unique C terminus. The conserved "VTDL" motif at the C terminus of these plexins binds to the N-terminal PDZ (PSD-95/Discs-large/ZO-1) domains of two related guanine nucleotide exchange factors (GEFs), PDZ-RhoGEF, and leukemia-associated RhoGEF (LARG) (12)(13)(14)(15)(16)(17). This interaction recruits PDZ-RhoGEF and LARG to the plasma membrane, where they promote the exchange of GDP for GTP on RhoA. GTP-bound RhoA binds its downstream effectors and contributes to plexin signaling (13)(14)(15)18). A recent study has shown that deletion of the C terminus of PlexinB2 causes defects in the development of the liver vasculature in mice, highlighting the critical role of the PDZ-RhoGEF/LARG-RhoA pathway in plexin function in vivo (19).More than 250 PDZ domains exist in the human proteome, con...

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Section: Resultssupporting

confidence: 65%

mentioning

confidence: 99%

Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ–RhoGEF

Pascoe

Gutowski

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This GAP domain is conserved quite highly throughout the plexin family. [25][26][27] In the cases of plexin-D1 and plexin-B1 it was demonstrated that most of the developmental effects of these plexins are lost if the function of this GAP domain is compromised. 28 Type-A plexins associate spontaneously to form homodimers 11,12 or heterodimers.…”

Section: Plexinsmentioning

confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling. Recent evidence suggests that semaphorins also fulfill important roles in the etiology of multiple forms of cancer. Some semaphorins have been found to function as bona-fide tumor suppressors and to inhibit tumor progression by various mechanisms while other semaphorins function as inducers and promoters of tumor progression. The semaphorin familyThe semaphorin family members are divided into 8 subclasses of which subclasses 1 and 2 contain invertebrate semaphorins while subclasses 3-7 contain the 22 vertebrate semaphorins. The 8th subclass contains viral semaphorins. In early publications, semaphorins were assigned confusing names. This situation was rectified by the adoption of a unified nomenclature in which sema is followed by the subclass number and by alphabetic designation within the subclass.1 Semaphorins are characterized by the presence of a »500 amino-acids long sema domain located close to their N-termini which is also present in semaphorin receptors of the plexin family, and by a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The sema domain is essential for semaphorin activity and plays a role in the determination of the receptor binding specificity.2 The sema domains of several different semaphorins were characterized by X-ray crystallography revealing a b propeller topology.3-5 Different semaphorin subclasses are characterized by class specific structural motifs. Thus, the vertebrate semaphorins belonging to classes 3, 4 and 7 contain immunoglobulin like domains, class-5 semaphorins contain thrombospondin repeats and class-3 semaphorins contain a basic domain. Class-3 semaphorins are the only vertebrate semaphorins produced as secreted proteins while other vertebrate semaphorins are membrane anchored or trans-membrane proteins that can be further processed into soluble forms by proteolytic cleavage (Fig.

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“…14,16,17 Likewise, crystal structure of the Plexin cytoplasmic region reveals that the Plexin GAP structure is comparable to that of canonical RasGAPs. 18,19 While much remains to be learned of this Plexin GAP activity and the differences in GAP specificity/activity between different Plexin family members, these results are exciting in light of the role of small GTPases in cytoskeletal regulation and adhesive interactions. For example, both Ras and Rap family small GTPases are known to activate Integrin-mediated cell adhesion, 11,14,17 and results indicate that Plexins decrease the level of active GTP-bound forms of these GTPases (reviewed in ref.…”

Section: Regulating Sema/plexin-mediated Small Gtpase Signaling To Gumentioning

confidence: 99%

“…14 Although a complete understanding on how Semas and Rho family GTPases contribute to the activation of the Plexin GAP awaits further study, Sema binding likely induces clustering of Plexins and GAP activity, 18,20,21 while GTPase binding also induces a conformational change in Plexin and increases the amount of Plexin at the cellular membrane.…”

Section: Small Gtpases Are Key Regulators Of Cytoskeletal and Adhesivmentioning

confidence: 99%

Regulating small G protein signaling to coordinate axon adhesion and repulsion

Yang

Terman²

2013

Small GTPases

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Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration

Cited by 78 publications

References 37 publications

Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ–RhoGEF

Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ–RhoGEF

The role of the semaphorins in cancer

Regulating small G protein signaling to coordinate axon adhesion and repulsion

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