Both the C-Terminal Polylysine Region and the Farnesylation of K-RasB Are Important for Its Specific Interaction with Calmodulin

Wu, Ling-Jia; Xu, Lirong; Liao, Jingling; Chen, Jie; Liang, Yi

doi:10.1371/journal.pone.0021929

Cited by 31 publications

(40 citation statements)

References 51 publications

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“…Several studies have examined the selective interaction between K-ras and Ca 2+ /CaM1112 and examined the K-ras-binding state(GTP versus GDP), which we have verified and confirmed (Supplementary Fig. 5b,c).…”

Section: Resultssupporting

confidence: 77%

A role for sorting nexin 27 in AMPA receptor trafficking

et al. 2014

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Sorting nexin 27 (SNX27), a PDZ domain-containing endosomal protein, was recently shown to modulate glutamate receptor recycling in Down’s syndrome. However, the precise molecular role of SNX27 in GluA1 trafficking is unclear. Here we report that SNX27 is enriched in dendrites and spines, along with recycling endosomes. Significantly, the mobilization of SNX27 along with recycling endosomes into spines was observed. Mechanistically, SNX27 interacts with K-ras GTPase via the RA domain; and following chemical LTP stimuli, K-ras is recruited to SNX27-enriched endosomes through a Ca2+/CaM-dependent mechanism, which in turn drives the synaptic delivery of homomeric GluA1 receptors. Impairment of SNX27 prevents LTP and associated trafficking of AMPARs. These results demonstrate a role for SNX27 in neuronal plasticity, provide a molecular explanation for the K-ras signal during LTP and identify SNX27 as the PDZ-containing molecular linker that couples the plasticity stimuli to the delivery of postsynaptic cargo.

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Section: Resultssupporting

confidence: 77%

A role for sorting nexin 27 in AMPA receptor trafficking

et al. 2014

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“…Targeting the allosteric lobe will require assays that detect binding at those sites in high-throughput screens, and the hypotheses derived from structural analysis of specific mutants regarding the activation of the allosteric switch need to be confirmed. Another unexplored area of opportunity is interaction between the C-terminal hypervariable region and switch II in K-RAS4B with calmodulin, which results in signal attenuation (81)(82)(83)(84). Although promotion of protein-protein interaction is not trivial, it is not unprecedented (85) and should be explored in the future.…”

Section: Discussionmentioning

confidence: 99%

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Marcus

Mattos

2015

Clinical Cancer Research

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The crystal structure of RAS was first solved 25 years ago. In spite of tremendous and sustained efforts, there are still no drugs in the clinic that directly target this major driver of human cancers. Recent success in the discovery of compounds that bind RAS and inhibit signaling has fueled renewed enthusiasm, and in-depth understanding of the structure and function of RAS has opened new avenues for direct targeting. To succeed, we must focus on the molecular details of the RAS structure and understand at a high-resolution level how the oncogenic mutants impair function. Structural networks of intramolecular communication between the RAS active site and membraneinteracting regions on the G-domain are disrupted in oncogenic mutants. Although conserved across the isoforms, these networks are near hot spots of protein-ligand interactions with amino acid composition that varies among RAS proteins. These differences could have an effect on stabilization of conformational states of interest in attenuating signaling through RAS. The development of strategies to target these novel sites will add a fresh direction in the quest to conquer RAS-driven cancers.

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“…The KRAS4b C-terminus has some propensity to form a helix [49], however, it lacks the hydrophobic anchor residues of the canonical CaM targets. Most, but not all studies have reported that CaM binding to KRAS4b requires farnesylation [43,44,46,[50][51][52][53][54][55], and there are discrepancies in the literature about whether or not the GTPase domain or the nucleotide to which it is bound (GTP versus GDP) plays a role in the interaction.…”

Section: Kras4bmentioning

confidence: 99%

“…There have been a number of studies performed to elucidate the nature of CaM binding to KRAS4b. Not surprisingly, earlier studies focused on probing the direct interaction between CaM and the GTPase-domain of KRAS and proposed this interaction is GTP-dependent [43,45,50,51]. On the other hand, other researchers reported negative evidence for this interaction and concluded that KRAS G-domain does not bind CaM [44,46,51,53,54].…”

Section: Structural Characterization Of Cam Binding To Kras4bmentioning

confidence: 99%

“…Not surprisingly, earlier studies focused on probing the direct interaction between CaM and the GTPase-domain of KRAS and proposed this interaction is GTP-dependent [43,45,50,51]. On the other hand, other researchers reported negative evidence for this interaction and concluded that KRAS G-domain does not bind CaM [44,46,51,53,54]. Recent in vitro biophysical and structural studies of the KRAS4b-CaM interaction [54,55] improved our understanding of this controversial interaction and revealed the detail of the CaM interaction with KRAS4b, which involves the farnesylated tail for binding to CaM.…”

Section: Structural Characterization Of Cam Binding To Kras4bmentioning

confidence: 99%

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A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization

Grant

Enomoto

Ikura

et al. 2020

IJMS

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Calmodulin (CaM) is a Ca 2+ -sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic 'anchor' residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca 2+ -binding motifs that form a Ca 2+ -induced hydrophobic pocket that binds an anchor residue. A central flexible linker allows CaM to accommodate diverse targets. Several reported CaM interactors lack these anchors but contain Lys/Arg-rich polybasic sequences adjacent to a lipidated N-or C-terminus. Ca 2+ -CaM binds the myristoylated N-terminus of CAP23/NAP22 with intimate interactions between the lipid and a surface comprised of the hydrophobic pockets of both lobes, while the basic residues make electrostatic interactions with the negatively charged surface of CaM. Ca 2+ -CaM binds farnesylcysteine, derived from the farnesylated polybasic C-terminus of KRAS4b, with the lipid inserted into the C-terminal lobe hydrophobic pocket. CaM sequestration of the KRAS4b farnesyl moiety disrupts KRAS4b membrane association and downstream signaling. Phosphorylation of basic regions of N-/C-terminal lipidated CaM targets can reduce affinity for both CaM and the membrane. Since both N-terminal myristoylated and C-terminal prenylated proteins use a Singly Lipidated Polybasic Terminus (SLIPT) for CaM binding, we propose these polybasic lipopeptide elements comprise a non-canonical CaM-binding motif.

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Both the C-Terminal Polylysine Region and the Farnesylation of K-RasB Are Important for Its Specific Interaction with Calmodulin

Cited by 31 publications

References 51 publications

A role for sorting nexin 27 in AMPA receptor trafficking

A role for sorting nexin 27 in AMPA receptor trafficking

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization

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