Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly

Or, Buonarati; Ap, Miller; Sj, Coultrap; Bayer, K. Ulrich; Reichow, Steve

doi:10.1101/2021.01.21.427643

Cited by 4 publications

(4 citation statements)

References 83 publications

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“…Kinetic differences are presumably mediated by conformational differences of various inactive and active states of the holoenzyme. However, the exact nature of these states is still under debate (Buonarati et al, 2021;Chao et al, 2011;Myers et al, 2017;Sloutsky et al, 2020). In our study, we confirm recent results that under steady-state conditions, the variable linker segment that is modulated by alternative splicing does not affect the cooperativity of the enzyme (Sloutsky et al, 2020), but modulates the maximal activity at optimal calmodulin concentrations.…”

Section: Discussionsupporting

confidence: 90%

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Franz

Weber

Preußner

et al. 2022

Preprint

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Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific Camk2β alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing a paradigm for cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9 we introduced a weaker human branch point into the mouse genome, resulting in human-like CAMK2B splicing in the brain of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled, species specific alternative splicing with a fundamental function in learning and memory.

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Section: Discussionsupporting

confidence: 90%

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Franz

Weber

Preußner

et al. 2022

Preprint

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“…The tether controlling this reaction consists of an IDR, the hub domain of the kinase, and another IDR. 7 In the bivalent interaction between the PDZ domains of PSD-95 and ionotropic glutamate receptors, the tether consists of the disordered C-terminal domain of one receptor subunit, the ion channel domain, and the disordered C-terminal tail of another receptor subunit. 8 The T h i s c o n t e n t i s connections that tether biochemical reactions thus vary beyond what is typically considered linkers and may include domains that have other functions.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In the auto-phosphorylation of calmodulin-dependent kinase II, the catalytic domain phosphorylates a regulatory region in a neighboring subunit. The tether controlling this reaction consists of an IDR, the hub domain of the kinase, and another IDR . In the bivalent interaction between the PDZ domains of PSD-95 and ionotropic glutamate receptors, the tether consists of the disordered C-terminal domain of one receptor subunit, the ion channel domain, and the disordered C-terminal tail of another receptor subunit .…”

Section: Introductionmentioning

confidence: 99%

Estimation of Effective Concentrations Enforced by Complex Linker Architectures from Conformational Ensembles

Kjærgaard

2022

Biochemistry

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Proteins and protein assemblies often tether interaction partners to strengthen interactions, to regulate activity through auto-inhibition or -activation, or to boost enzyme catalysis. Tethered reactions are regulated by the architecture of the tether, which defines an effective concentration of the interactor. Effective concentrations can be estimated theoretically for simple linkers via polymer models, but there is currently no general method for estimating effective concentrations for complex linker architectures consisting of both flexible and folded domains. We describe how effective concentrations can be estimated computationally for any protein linker architecture by defining a realistic conformational ensemble. We benchmark against prediction from a worm-like chain and values measured by competition experiments and find minor differences likely due to excluded volume effects. Systematic variation of the properties of flexible and folded segments shows that the effective concentration is mainly determined by the combination of the total length of flexible segments and the distance between the termini of the folded domains. We show that a folded domain in a disordered linker can increase the effective concentration beyond what can be achieved by a fully disordered linker by focusing the end-to-end distance at the appropriate spacing. This suggests that complex linker architecture may have advantages over simple flexible linkers and emphasizes that annotation as a linker should depend on the molecular context.

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“…The tether controlling this reaction consists of an IDR, the hub domain of the kinase, and another IDR. 7 In the bivalent interaction between the PDZ domains of PSD-95 and ionotropic glutamate receptors, the tether consists of the disordered C-terminal domain of one receptor subunit, the ion channel domain, and the disordered C-terminal tail of another receptor subunit. 8 The connections that tether biochemical reactions thus vary beyond what is typically considered linkers and may include domains that have other functions.…”

Section: Introductionmentioning

confidence: 99%

Estimation of effective concentrations enforced by complex linker architectures from conformational ensembles

Kjærgaard

2021

Preprint

View full text Add to dashboard Cite

Proteins and protein assemblies often tether interaction partners to strengthen interactions, to regulate activity through auto-inhibition or -activation, or to boost enzyme catalysis. Tethered reactions are regulated by the architecture of tether, which define an effective concentration of the interactors. Effective concentrations can be estimated theoretically for simple linkers via polymer models, but there is currently no general method for estimating effective concentrations for complex linker architectures consisting of both flexible and folded domains. We describe how effective concentrations can be estimated computationally for any protein linker architecture by defining a realistic conformational ensemble. We benchmark against prediction from a worm-like chain and values measured by competition experiments, and find minor differences likely due to excluded volume effects. Systematic variation of the properties of flexible and folded segments show that the effective concentration is mainly determined by the combination of the total length of flexible segments and the distance between termini of the folded domains. We show that a folded domain in a disordered linker can increase the effective concentration beyond what can be achieved by a fully disordered linker by focusing the end-to-end distance at the appropriate spacing. This suggest that complex linker architecture may have advantages over simple flexible linker, and emphasize that annotation as a linker should depend on the molecular context.

show abstract

Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly

Cited by 4 publications

References 83 publications

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Estimation of Effective Concentrations Enforced by Complex Linker Architectures from Conformational Ensembles

Estimation of effective concentrations enforced by complex linker architectures from conformational ensembles

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