Proline cis/trans Isomerization in Intrinsically Disordered Proteins and Peptides

Sebák, Fanni; Szolomájer, János; Papp, Nándor; Tóth, Gábor K.; Bodor, Andrea

doi:10.31083/j.fbl2806127

Cited by 6 publications

(2 citation statements)

References 36 publications

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“…In the trans configuration, proline has ω = 180°, while in cis , ω = 0°. A transition of cis to a syn (ω = 90°) state needs to overcome a ∼30 kcal mol –1 energy barrier, leading to a predominantly trans conformation. , Experimental measurements consistently demonstrate slow cis-to-trans conversion rates. Phosphorylation affects cis–trans isomerization rates.…”

Section: Discussionmentioning

confidence: 99%

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Liu,

Jang,

Nussinov

2024

J. Phys. Chem. B

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SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates a regulatory phosphorylation site in EGFR that serves as the binding site to RasGAP (RASA1 or p120RasGAP). RASA1 is activated by binding to the EGFR phosphate group. Active RASA1 deactivates Ras by hydrolyzing Ras-bound GTP to GDP. Thus, SHP2 dephosphorylation of EGFR effectively prevents RASA1-mediated deactivation of Ras, thereby stimulating proliferation. Despite knowledge of this vital regulation in cell life, mechanistic in-depth structural understanding of the involvement of SHP2, EGFR, and RASA1 in the Ras/MAPK pathway has largely remained elusive. Here we elucidate the interactions, the factors influencing EGFR’s recruitment of RASA1, and SHP2’s recognition of the substrate site in EGFR. We reveal that RASA1 specifically interacts with the DEpY992LIP motif in EGFR featuring a proline residue at the +3 position C-terminal to pY primarily through its nSH2 domain. This interaction is strengthened by the robust attraction of two acidic residues, E991 and D990, of EGFR to two basic residues in the BC-loop near the pY-binding pocket of RASA1’s nSH2. In the stable precatalytic state of SHP2 with EGFR (DADEpY992LIPQ), the E-loop of SHP2’s active site favors the interaction with the (−2)-position D990 and (−4)-position D988 N-terminal to pY992 in EGFR, while the pY-loop constrains the (+4)-position Q996 C-terminal to pY992. These specific interactions not only provide a structural basis for identifying negative regulatory sites in other RTKs but can inform selective, high-affinity active-site SHP2 inhibitors tailored for SHP2 mutants.

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Section: Discussionmentioning

confidence: 99%

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Liu,

Jang,

Nussinov

2024

J. Phys. Chem. B

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“…After looking at many sequences of functional tau fragments, they did not find high number of cis conformation in Thr231–Pro232 segment (Ahuja et al, 2016). Recently, an NMR study showed that at least in some IDPs, ratio of cis / trans conformations of Pro depends upon occurrence of aromatic and charged side chains in the neighboring sequences (Sebak et al, 2023). Also, Mateos et al (2020) studied an IDP osteopontin by NMR and found Pro having a role in nucleation of its central compact region.…”

Section: Some Amino Acids Enable Intrinsic Disorder In Proteinsmentioning

confidence: 99%

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Gupta,

Uversky

2024

Protein Science

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The rationale for replacing the old binary of structure–function with the trinity of structure, disorder, and function has gained considerable ground in recent years. A continuum model based on the expanded form of the existing paradigm can now subsume importance of both conformational flexibility and intrinsic disorder in protein function. The disorder is actually critical for understanding the protein–protein interactions in many regulatory processes, formation of membrane‐less organelles, and our revised notions of specificity as amply illustrated by moonlighting proteins. While its importance in formation of amyloids and function of prions is often discussed, the roles of intrinsic disorder in infectious diseases and protein function under extreme conditions are also becoming clear. This review is an attempt to discuss how our current understanding of protein function, specificity, and evolution fit better with the continuum model. This integration of structure and disorder under a single model may bring greater clarity in our continuing quest for understanding proteins and molecular mechanisms of their functionality.

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Proline, a unique amino acid whose polymer, polyproline II helix, and its analogues are involved in many biological processes: a review

Umumararungu,

Gahamanyi,

Mukiza

et al. 2024

Amino Acids

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Proline cis/trans Isomerization in Intrinsically Disordered Proteins and Peptides

Cited by 6 publications

References 36 publications

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Proline, a unique amino acid whose polymer, polyproline II helix, and its analogues are involved in many biological processes: a review

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