Electrostatic and Hydrophobic Interactions Differentially Tune Membrane Binding Kinetics of the C2 Domain of Protein Kinase Cα

Scott, A. M.; Antal, Corina E.; Newton, Alexandra C.

doi:10.1074/jbc.m113.467456

Cited by 23 publications

(25 citation statements)

References 50 publications

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“…In several MAPs, the binding to MTs is mediated by positively charged motifs, most likely via electrostatic interaction with acidic tail motifs of tubulin subunits (Smith et al, 2001;Mishima et al, 2007;Drevensek et al, 2012;Roll-Mecak, 2015). Similarly, membrane-binding motifs used to anchor proteins to the acidic phospholipid surface of membranes often consist of basic amino acids (Goldenberg and Steinberg, 2010;Scott et al, 2013), and nuclear localization signals require core basic residues for their activity (Kosugi et al, 2009). The high basic pI of IQD proteins (;10.3), which is a hallmark of the family , suggests that electrostatic interaction contributes to the MT and PM attachment of IQD proteins, and chargeplot analysis reveals the occurrence of basic patches in all 33 Arabidopsis IQD members (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

et al. 2017

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ORCID IDs: 0000-0002-3493-4800 (K.B.); 0000-0002-7146-043X (B.M.).Calcium (Ca 2+ ) signaling and dynamic reorganization of the cytoskeleton are essential processes for the coordination and control of plant cell shape and cell growth. Calmodulin (CaM) and closely related calmodulin-like (CML) polypeptides are principal sensors of Ca 2+ signals. CaM/CMLs decode and relay information encrypted by the second messenger via differential interactions with a wide spectrum of targets to modulate their diverse biochemical activities. The plant-specific IQ67 DOMAIN (IQD) family emerged as possibly the largest class of CaM-interacting proteins with undefined molecular functions and biological roles. Here, we show that the 33 members of the IQD family in Arabidopsis (Arabidopsis thaliana) differentially localize, using green fluorescent protein (GFP)-tagged proteins, to multiple and distinct subcellular sites, including microtubule (MT) arrays, plasma membrane subdomains, and nuclear compartments. Intriguingly, the various IQD-specific localization patterns coincide with the subcellular patterns of IQD-dependent recruitment of CaM, suggesting that the diverse IQD members sequester Ca 2+ -CaM signaling modules to specific subcellular sites for precise regulation of Ca 2+ -dependent processes. Because MT localization is a hallmark of most IQD family members, we quantitatively analyzed GFP-labeled MT arrays in Nicotiana benthamiana cells transiently expressing GFP-IQD fusions and observed IQD-specific MT patterns, which point to a role of IQDs in MT organization and dynamics. Indeed, stable overexpression of select IQD proteins in Arabidopsis altered cellular MT orientation, cell shape, and organ morphology. Because IQDs share biochemical properties with scaffold proteins, we propose that IQD families provide an assortment of platform proteins for integrating CaM-dependent Ca 2+ signaling at multiple cellular sites to regulate cell function, shape, and growth.

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Section: Discussionmentioning

confidence: 99%

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

et al. 2017

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“…The main phospholipids in microbial cell membranes are PG and PE. The anionic lipid DPG is a minor component (Ͻ5%) of Gram-negative membranes but a major component of Gram-positive membranes (35)(36)(37)(38). It is reasonable to assume that the main effects underlying the interactions between MIMs and the cytoplasmic membrane are driven by major membrane components.…”

Section: Aminoacylated Phospholipidsmentioning

confidence: 99%

Oligopolyphenylenevinylene-Conjugated Oligoelectrolyte Membrane Insertion Molecules Selectively Disrupt Cell Envelopes of Gram-Positive Bacteria

Hinks

Poh

Chu

et al. 2015

Appl Environ Microbiol

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The modification of microbial membranes to achieve biotechnological strain improvement with exogenous small molecules, such as oligopolyphenylenevinylene-conjugated oligoelectrolyte (OPV-COE) membrane insertion molecules (MIMs), is an emerging biotechnological field. Little is known about the interactions of OPV-COEs with their target, the bacterial envelope. We studied the toxicity of three previously reported OPV-COEs with a selection of Gram-negative and Gram-positive organisms and demonstrated that Gram-positive bacteria are more sensitive to OPV-COEs than Gram-negative bacteria. Transmission electron microscopy demonstrated that these MIMs disrupt microbial membranes and that this occurred to a much greater degree in Gram-positive organisms. We used a number of mutants to probe the nature of MIM interactions with the microbial envelope but were unable to align the membrane perturbation effects of these compounds to previously reported membrane disruption mechanisms of, for example, cationic antimicrobial peptides. Instead, the data support the notion that OPV-COEs disrupt microbial membranes through a suspected interaction with diphosphatidylglycerol (DPG), a major component of Grampositive membranes. The integrity of model membranes containing elevated amounts of DPG was disrupted to a greater extent by MIMs than those prepared from Escherichia coli total lipid extracts alone.

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“…Conventional PKCs are allosterically activated by binding to two second messengers: Ca 2+ and diacylglycerol. Binding of the C2 domain to Ca 2+ targets the kinase to the plasma membrane through hydrophobic interactions that drive binding to anionic phospholipids and through electrostatic interactions that contribute to retention of the C2 domain to membranes [12]. Once at the membrane, one of PKC’s C1 domains can then find and bind DAG, and event that provides the necessary energy to expel the pseudosubstrate and activate PKC [13].…”

Section: Regulation By Second Messengersmentioning

confidence: 99%

“…Firstly, conventional and novel PKCs predominantly translocate to different membranes. Conventional PKCs translocate to and are active at the plasma membrane because their Ca 2+ -binding C2 domain targets them there via PIP 2 , where they can then find diacylglycerol [12]. Novel PKCs do not have a functional C2 domain but have a C1A domain that has a 100-fold higher affinity for DAG [14] and, therefore, they translocate to DAG-rich endomembranes such as the Golgi.…”

Section: Regulation By Second Messengersmentioning

confidence: 99%

“…Novel PKCs do not have a functional C2 domain but have a C1A domain that has a 100-fold higher affinity for DAG [14] and, therefore, they translocate to DAG-rich endomembranes such as the Golgi. Indeed, impairing the ability of the C2 domain of PKCα to bind membranes forces it to the Golgi instead, as the C1 domain interaction becomes the dominant force [12]. Secondly, the kinetics of activation differ between conventional and novel PKCs.…”

Section: Regulation By Second Messengersmentioning

confidence: 99%

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Tuning the signalling output of protein kinase C

Antal

Newton

2014

Biochemical Society Transactions

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Precise control of the amplitude of protein kinase C signaling is essential for maintaining cellular homeostasis, and disruption of this control leads to pathophysiological states such as cancer and neurodegeneration. This amplitude is precisely tuned by multiple inputs that regulate the amount of protein kinase C in the cell, its ability to sense its allosteric activator diacylglycerol, and protein scaffolds that coordinate access to substrates. Key to regulation of the signaling output of most protein kinase C isozymes is the ability of cytosolic enzyme to respond to the membrane-embedded lipid second messenger, diacylglycerol, in a dynamic range that prevents signaling in the absence of agonists but allows efficient signaling in response to small changes in diacylglycerol. This review discusses the regulatory inputs that control the spatiotemporal dynamics of protein kinase C signaling, focusing on conventional and novel PKC isozymes.

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Electrostatic and Hydrophobic Interactions Differentially Tune Membrane Binding Kinetics of the C2 Domain of Protein Kinase Cα

Cited by 23 publications

References 50 publications

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

The IQD Family of Calmodulin-Binding Proteins Links Calcium Signaling to Microtubules, Membrane Subdomains, and the Nucleus

Oligopolyphenylenevinylene-Conjugated Oligoelectrolyte Membrane Insertion Molecules Selectively Disrupt Cell Envelopes of Gram-Positive Bacteria

Tuning the signalling output of protein kinase C

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