Direct Interaction between Calmodulin and the Grb7 RA-PH Domain

Watson, G.M.; Wilce, Jacqueline A.

doi:10.3390/ijms21041336

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…Itk (interleukin-2-inducible tyrosine kinase) belongs to the Tec kinase family ( 84 ). Also, a more recent study that aimed to investigate the direct interaction between CaM and the growth receptor bond 7 (Grb7) protein showed that CaM interacts with the PHD of Grb7 ( 85 ). There, CaM’s peculiar binding motif was mapped to the β -sheet and not an α -helical region ( 85 ).…”

Section: Discussionmentioning

confidence: 99%

“…Also, a more recent study that aimed to investigate the direct interaction between CaM and the growth receptor bond 7 (Grb7) protein showed that CaM interacts with the PHD of Grb7 ( 85 ). There, CaM’s peculiar binding motif was mapped to the β -sheet and not an α -helical region ( 85 ). The NMR CSP data for the Akt PHD indicated that it interacts with CaM via the β 1- β 2 and β 6- β 7 loops ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

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The structural basis of Akt PH domain interaction with calmodulin

Weako

Jang

Keskin

et al. 2021

Biophysical Journal

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Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP 3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a b-strand rather than an a-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP 4 , the polar head of PIP 3 , weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3Ka activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The structural basis of Akt PH domain interaction with calmodulin

Weako

Jang

Keskin

et al. 2021

Biophysical Journal

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“…26 La región central de GRB7 tiene un dominio de cerca de 300 aminoácidos que muestran una alta homología con un gen de Caenorhabditis elegans, el gen Mig-10. 27 Este ha sido involucrado en la migración de células neuronales durante el desarrollo, por lo cual se ha sugerido un rol de GRB7 en la regulación de la migración de células mamíferas. 28 La región central contiene tres dominios: RA (asociado a Ras) por lo cual se cree que GRB7 interactúa con las GTPAsas de la superfamilia Ras y de esta forma regula la progresión del cáncer, un dominio de homología a pleckstrina (PH) y el dominio BPS (entre PH y SH2) el cual interactúa principalmente con el receptor de insulina activado en el dominio SH2.…”

Section: G R B 7 E S T Ru C T U R a Y U B I Cac I ó Nunclassified

La proteína 7 unida al receptor del factor de crecimiento (GRB7) en cáncer de mama

et al. 2022

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El cáncer de mama debe considerarse como un problema de salud pública ya que es la causa principal de muerte en mujeres en el mundo. Se conoce que es multifactorial y heterogéneo de manera que cada tumor tiene características genéticas y moleculares propias, lo cual se refleja en el comportamiento clínico, respuesta al tratamiento y pronóstico. La proteína 7 unida al receptor del factor de crecimiento (GRB7) hace parte de un grupo de proteínas GRB que median la interacción entre receptores tirosina cinasa y proteínas efectoras en algunas vías de señalización involucradas en transducción de señales, migración celular y angiogénesis. Esta proteína es codificada por el gen GRB7 localizado en el cromosoma 17 en el locus 17q11–21, cerca del gen ERBB2, lo que sugiere coamplificación y coexpresión de estos dos genes en el desarrollo del cáncer. Se ha visto que la proteína GRB7 por sí sola está presente en la biología molecular implícita del cáncer de mama, interviniendo en la proliferación y migración celular facilitando así la invasión y posibles metástasis. Se considera como un factor de mal pronóstico en esta enfermedad.

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“…The Ca 2+ -bound C-lobe and Ca 2+ -free N-lobe bind distinct sites, which leads to stabilization of the adenylyl cyclase catalytic site [26] (Figure 1). CaM interacts with the Ras-association (RA) and pleckstrin homology (PH) domains of the adaptor protein growth factor receptor-bound protein 7 (Grb7) in a calcium-dependent manner and regulates its subcellular localization [27,28]. It was proposed that CaM binding may open the Grb7 structure, facilitating the RA and PH domains to interact with activated RAS and the membrane, respectively.…”

Section: Mechanisms By Which Ca 2+ -Cam Regulates Target Proteinsmentioning

confidence: 99%

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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Direct Interaction between Calmodulin and the Grb7 RA-PH Domain

Cited by 5 publications

References 27 publications

The structural basis of Akt PH domain interaction with calmodulin

The structural basis of Akt PH domain interaction with calmodulin

La proteína 7 unida al receptor del factor de crecimiento (GRB7) en cáncer de mama

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

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