Phosphorylation of the arginine/serine repeats of lamin B receptor by SRPK1—Insights from molecular dynamics simulations

Sellis, Diamantis; Drosou, Victoria; Vlachakis, Dimitriοs; Voukkalis, Nikolas; Giannakouŕos, Thomas; Vlassi, Metaxia

doi:10.1016/j.bbagen.2011.10.010

Cited by 34 publications

(59 citation statements)

References 43 publications

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“…Previous in vitro phosphorylation and dephosphorylation assays have shown that LBR is phosphorylated by CDK and SRPKs and is dephosphorylated by PP1γ1 at its N-terminal region (Ito et al, 2007; Lu et al, 2010; Nikolakaki et al, 1997, 1996; Papoutsopoulou et al, 1999; Sellis et al, 2012; Takano et al, 2004; Tseng and Chen, 2011; Tsianou et al, 2009). To examine whether LBR phosphorylation is also regulated by CDK and SRPKs in cells, cells were treated with roscovitine, a CDK inhibitor; SRPIN340, an SRPK inhibitor; or both inhibitors, and then the phosphorylation status of LBR was analyzed using Phos-tag western blotting.…”

Section: Resultsmentioning

confidence: 99%

“…Previous in vitro phosphorylation assays have shown that LBR is phosphorylated at S71 and S86 by CDK (Ito et al, 2007; Lu et al, 2010; Tseng and Chen, 2011) and at serine residues within the RS domain by SRPKs (Nikolakaki et al, 1997, 1996; Papoutsopoulou et al, 1999; Sellis et al, 2012; Takano et al, 2004; Tsianou et al, 2009). To investigate whether these serine residues of LBR are phosphorylated in cells, we generated a series of unphosphorylated mutants that are depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The N-terminal region of LBR comprises a Tudor domain (also called the globular I domain) and a globular II domain, which are linked by a hinge region (Liokatis et al, 2012; Ye et al, 1997). The hinge region contains a nuclear localization signal (NLS), which is required for the interaction with importin β (Ma et al, 2007), and an arginine-serine repeat (RS) domain, which consists of multiple repeats of arginine and serine residues (Sellis et al, 2012). The entire N-terminal region is required for interaction with lamin B (Ye and Worman, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Previous in vitro assays have shown that LBR is phosphorylated at residues S71 and S86 by cyclin-dependent kinase (CDK) (Lu et al, 2010; Nikolakaki et al, 1997; Tseng and Chen, 2011), and serine residues within the RS domain are phosphorylated by serine/arginine protein kinases 1 and 2 (SRPK1 and SRPK2, respectively) (Nikolakaki et al, 1997, 1996; Sellis et al, 2012; Tsianou et al, 2009). However, phosphorylation at these sites is removed by the γ1 isoform of protein serine/threonine phosphatase-1 (PP1γ1) (Ito et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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ELYS regulates the localization of LBR by modulating its phosphorylation state

Mimura¹,

Takagi²,

Clever

et al. 2016

Journal of Cell Science

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Lamin B receptor (LBR), an inner nuclear membrane (INM) protein, contributes to the functional integrity of the nucleus by tethering heterochromatin to the nuclear envelope. We have previously reported that the depletion of embryonic large molecule derived from yolk sac (ELYS; also known as AHCTF1), a component of the nuclear pore complex, from cells perturbs the localization of LBR to the INM, but little is known about the underlying molecular mechanism. In this study, we found that the depletion of ELYS promoted LBR phosphorylation at the residues known to be phosphorylated by cyclin-dependent kinase (CDK) and serine/arginine protein kinases 1 and 2 (SRPK1 and SRPK2, respectively). These phosphorylation events were most likely to be counter-balanced by protein phosphatase 1 (PP1), and the depletion of PP1 from cells consistently caused the mislocalization of LBR. These observations point to a new mechanism regulating the localization of LBR, which is governed by an ELYS-mediated phosphorylation network. This phosphorylation-dependent coordination between INM proteins and the nuclear pore complex might be important for the integrity of the nucleus.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ELYS regulates the localization of LBR by modulating its phosphorylation state

Mimura¹,

Takagi²,

Clever

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…[22], by combining NMR measurement and molecular dynamics(MD) simulations for serine/arginine-rich proteins, the authors showed that phosphorylation of serine switches the serine/argininerich domain from a fully disordered state to a partially rigidified structure, demonstrating a dynamic switching mechanism. The effects of phosphorylation on protein-protein interactions, the cis-trans isomerization of peptidyl-prolyl bonds, and protein global structures have also been investigated [23][24][25]. These works provided valuable information about the effects of phosphorylation on protein conformational and dynamical features.…”

Section: Introductionmentioning

confidence: 99%

Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine

Gao

Zhang

et al. 2016

J Biol Phys

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Each amino acid has its intrinsic propensity for certain local backbone conformations, which can be further modulated by the physicochemical environment and post-translational modifications. In this work, we study the effects of phosphorylation on the intrinsic propensity for different local backbone conformations of serine/threonine by molecular dynamics simulations. We showed that phosphorylation has very different effects on the intrinsic propensity for certain local backbone conformations for the serine and threonine. The phosphorylation of serine increases the propensity of forming polyproline II, whereas that of threonine has the opposite effect. Detailed analysis showed that such different responses to phosphorylation mainly arise from their different perturbations to the backbone hydration and the geometrical constraints by forming sidechain-backbone hydrogen bonds due to phosphorylation. Such an effect of phosphorylation on backbone conformations can be crucial for understanding the molecular mechanism of phosphorylation-regulated protein structures/dynamics and functions.

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Community analysis of large‐scale molecular dynamics simulations elucidated dynamics‐driven allostery in tyrosine kinase 2

Lesgidou,

Vlassi

2023

Proteins

Self Cite

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TYK2 is a nonreceptor tyrosine kinase, member of the Janus kinases (JAK), with a central role in several diseases, including cancer. The JAKs' catalytic domains (KD) are highly conserved, yet the isolated TYK2‐KD exhibits unique specificities. In a previous work, using molecular dynamics (MD) simulations of a catalytically impaired TYK2‐KD variant (P1104A) we found that this amino acid change of its JAK‐characteristic insert (αFG), acts at the dynamics level. Given that structural dynamics is key to the allosteric activation of protein kinases, in this study we applied a long‐scale MD simulation and investigated an active TYK2‐KD form in the presence of adenosine 5′‐triphosphate and one magnesium ion that represents a dynamic and crucial step of the catalytic cycle, in other protein kinases. Community analysis of the MD trajectory shed light, for the first time, on the dynamic profile and dynamics‐driven allosteric communications within the TYK2‐KD during activation and revealed that αFG and amino acids P1104, P1105, and I1112 in particular, hold a pivotal role and act synergistically with a dynamically coupled communication network of amino acids serving intra‐KD signaling for allosteric regulation of TYK2 activity. Corroborating our findings, most of the identified amino acids are associated with cancer‐related missense/splice‐site mutations of the Tyk2 gene. We propose that the conformational dynamics at this step of the catalytic cycle, coordinated by αFG, underlie TYK2‐unique substrate recognition and account for its distinct specificity. In total, this work adds to knowledge towards an in‐depth understanding of TYK2 activation and may be valuable towards a rational design of allosteric TYK2‐specific inhibitors.

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Phosphorylation of the arginine/serine repeats of lamin B receptor by SRPK1—Insights from molecular dynamics simulations

Cited by 34 publications

References 43 publications

ELYS regulates the localization of LBR by modulating its phosphorylation state

ELYS regulates the localization of LBR by modulating its phosphorylation state

Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine

Community analysis of large‐scale molecular dynamics simulations elucidated dynamics‐driven allostery in tyrosine kinase 2

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