pH-Dependent Compaction of the Intrinsically Disordered Poly-E Motif in Titin

Manukian, Sophia; Lindberg, Gerrick E.; Punch, Emily; Mudiyanselage, Sudarshi Premawardhana Dassanayake; Gage, Matthew J.

doi:10.3390/biology11091302

Cited by 2 publications

(1 citation statement)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These proteins lack a well-defined tertiary structure under physiological conditions, but many can form structures or structural ensembles under certain conditions [ 2 ]. The propensity of these proteins to switch conformation upon either interaction with ligands, post-translational modification, or change in ionic strength or pH, allows them to play crucial roles in cell signaling and regulation [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Many IDPs/IDRs have been reported to be associated with human diseases such as cardiovascular disease, neurodegenerative disease, diabetes, and cancer [ 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Enhancing the Conformational Stability of the cl-Par-4 Tumor Suppressor via Site-Directed Mutagenesis

et al. 2023

View full text Add to dashboard Cite

Intrinsically disordered proteins play important roles in cell signaling, and dysregulation of these proteins is associated with several diseases. Prostate apoptosis response-4 (Par-4), an approximately 40 kilodalton proapoptotic tumor suppressor, is a predominantly intrinsically disordered protein whose downregulation has been observed in various cancers. The caspase-cleaved fragment of Par-4 (cl-Par-4) is active and plays a role in tumor suppression by inhibiting cell survival pathways. Here, we employed site-directed mutagenesis to create a cl-Par-4 point mutant (D313K). The expressed and purified D313K protein was characterized using biophysical techniques, and the results were compared to that of the wild-type (WT). We have previously demonstrated that WT cl-Par-4 attains a stable, compact, and helical conformation in the presence of a high level of salt at physiological pH. Here, we show that the D313K protein attains a similar conformation as the WT in the presence of salt, but at an approximately two times lower salt concentration. This establishes that the substitution of a basic residue for an acidic residue at position 313 alleviates inter-helical charge repulsion between dimer partners and helps to stabilize the structural conformation.

show abstract

Section: Introductionmentioning

confidence: 99%

Enhancing the Conformational Stability of the cl-Par-4 Tumor Suppressor via Site-Directed Mutagenesis

et al. 2023

View full text Add to dashboard Cite

show abstract

The Disorderly Nature of Caliciviruses

Young,

McSweeney,

Edwards

et al. 2024

Viruses

View full text Add to dashboard Cite

An intrinsically disordered protein (IDP) or region (IDR) lacks or has little protein structure but still maintains function. This lack of structure creates flexibility and fluidity, allowing multiple protein conformations and potentially transient interactions with more than one partner. Caliciviruses are positive-sense ssRNA viruses, containing a relatively small genome of 7.6–8.6 kb and have a broad host range. Many viral proteins are known to contain IDRs, which benefit smaller viral genomes by expanding the functional proteome through the multifunctional nature of the IDR. The percentage of intrinsically disordered residues within the total proteome for each calicivirus type species can range between 8 and 23%, and IDRs have been experimentally identified in NS1-2, VPg and RdRP proteins. The IDRs within a protein are not well conserved across the genera, and whether this correlates to different activities or increased tolerance to mutations, driving virus adaptation to new selection pressures, is unknown. The function of norovirus NS1-2 has not yet been fully elucidated but includes involvement in host cell tropism, the promotion of viral spread and the suppression of host interferon-λ responses. These functions and the presence of host cell-like linear motifs that interact with host cell caspases and VAPA/B are all found or affected by the disordered region of norovirus NS1-2. The IDRs of calicivirus VPg are involved in viral transcription and translation, RNA binding, nucleotidylylation and cell cycle arrest, and the N-terminal IDR within the human norovirus RdRP could potentially drive liquid–liquid phase separation. This review identifies and summarises the IDRs of proteins within the Caliciviridae family and their importance during viral replication and subsequent host interactions.

show abstract

pH-Dependent Compaction of the Intrinsically Disordered Poly-E Motif in Titin

Cited by 2 publications

References 31 publications

Enhancing the Conformational Stability of the cl-Par-4 Tumor Suppressor via Site-Directed Mutagenesis

Enhancing the Conformational Stability of the cl-Par-4 Tumor Suppressor via Site-Directed Mutagenesis

The Disorderly Nature of Caliciviruses

Contact Info

Product

Resources

About