Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Sun, Bin; Kekenes‐Huskey, Peter M.

doi:10.1017/s003358352300001x

Cited by 5 publications

(5 citation statements)

References 501 publications

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“…IDRs are not merely flexible but have envolved to exert unique functions such as allowing rapid and reversal PPI and acting as recognition motifs. 47,48 Our simulation data suggest that p53's IDRs play multiple roles in fine-tuning the PPI. IDPs are well-known to accelerate protein binding rates through the "fly-casting" mechanism 49 which states that dynamic IDP increases the searching radius to capture binding partner.…”

Section: Discussionmentioning

confidence: 86%

Reconciling ASPP-p53 Binding Mode Discrepancies through an Ensemble Binding Framework that Bridges Crystallography and NMR Data

Liu,

Huang,

Zhang

et al. 2023

Preprint

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ASPP2 and iASPP bind to p53 through their conserved ANK-SH3 domains to respectively promote and inhibit p53-dependent cell apoptosis. While crystallography has indicated that these two proteins employ distinct surfaces of their ANK-SH3 domains to bind to p53, solution NMR data has suggested similar surfaces. In this study, we employed multi-scale molecular dynamics (MD) combined with free energy calculations to reconcile the discrepancy in the binding modes. We demonstrated that the binding mode based solely on a single crystal structure does not enable iASPP’s RT loop to engage with p53’s C-terminal linker—a verified interaction. Instead, an ensemble of simulated iASPP-p53 complexes facilitates this interaction. We showed that the ensemble-average inter-protein contacting residues and NMR-detected interfacial residues align well with ASPP proteins, and the ensemble-average binding free energies better match experimental Kd values compared to single crystallgarphy-determined binding mode. For iASPP, the sampled ensemble complexes can be grouped into two classes, resembling the binding modes determined by crystallography and solution NMR. We thus propose that crystal packing shifts the equilibrium of binding modes towards the crystallographydetermined one. Lastly, we show that the ensemble binding complexes are sensitive to p53’s intrinsically disordered regions (IDRs), attesting to experimental observations that these IDRs contribute to biological functions. Our results provide a dynamic and ensemble perspective for scrutinizing these important cancer-related protein-protein interactions (PPIs).

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Section: Discussionmentioning

confidence: 86%

Reconciling ASPP-p53 Binding Mode Discrepancies through an Ensemble Binding Framework that Bridges Crystallography and NMR Data

Liu,

Huang,

Zhang

et al. 2023

Preprint

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“…S3F) resembling a phase diagram to categorize these folds as a function of the fractions of negatively charged ( y axis) and positively charged amino acids ( x axis). Sun and Kekenes-Huskey ( 17 ) categorized the intrinsically disordered regions of cTnI (TNNI3), and according to this schematic, the C-terminal domain rests on the border between R2 (coils/premolten globules) and R3 (hairpins/coils/chimera). In fig.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

Donkervoort,

van de Locht,

Ronchi

et al. 2024

Sci. Transl. Med.

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Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast ( TNNI2 ) and TnI-slow ( TNNI1 ), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca 2+ ] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca 2+ ], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

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“…IDRs are not merely flexible but have envolved to exert unique functions such as allowing rapid and reversible PPI and acting as recognition motifs [ 47 , 48 ]. Our simulation data suggest that p53’s IDRs play multiple roles in fine-tuning the PPI.…”

Section: Discussionmentioning

confidence: 99%

Reconciling ASPP-p53 binding mode discrepancies through an ensemble binding framework that bridges crystallography and NMR data

Liu,

Huang,

Zhang

et al. 2024

PLoS Comput Biol

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ASPP2 and iASPP bind to p53 through their conserved ANK-SH3 domains to respectively promote and inhibit p53-dependent cell apoptosis. While crystallography has indicated that these two proteins employ distinct surfaces of their ANK-SH3 domains to bind to p53, solution NMR data has suggested similar surfaces. In this study, we employed multi-scale molecular dynamics (MD) simulations combined with free energy calculations to reconcile the discrepancy in the binding modes. We demonstrated that the binding mode based solely on a single crystal structure does not enable iASPP’s RT loop to engage with p53’s C-terminal linker—a verified interaction. Instead, an ensemble of simulated iASPP-p53 complexes facilitates this interaction. We showed that the ensemble-average inter-protein contacting residues and NMR-detected interfacial residues qualitatively overlap on ASPP proteins, and the ensemble-average binding free energies better match experimental KD values compared to single crystallgarphy-determined binding mode. For iASPP, the sampled ensemble complexes can be grouped into two classes, resembling the binding modes determined by crystallography and solution NMR. We thus propose that crystal packing shifts the equilibrium of binding modes towards the crystallography-determined one. Lastly, we showed that the ensemble binding complexes are sensitive to p53’s intrinsically disordered regions (IDRs), attesting to experimental observations that these IDRs contribute to biological functions. Our results provide a dynamic and ensemble perspective for scrutinizing these important cancer-related protein-protein interactions (PPIs).

show abstract

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Cited by 5 publications

References 501 publications

Reconciling ASPP-p53 Binding Mode Discrepancies through an Ensemble Binding Framework that Bridges Crystallography and NMR Data

Reconciling ASPP-p53 Binding Mode Discrepancies through an Ensemble Binding Framework that Bridges Crystallography and NMR Data

Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

Reconciling ASPP-p53 binding mode discrepancies through an ensemble binding framework that bridges crystallography and NMR data

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