Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0847097 (acidity)
15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solvation of protein surface charges plays an important role for the protonation states of titratable surface groups and is routinely incorporated in low dielectric protein models using surface accessible areas. For many-body protein simulations, however, such dielectric boundary methods are rarely tractable and a greater level of simplification is desirable. In this work, we scrutinize how charges on a high dielectric surface are affected by the nonpolar interior core of the protein. A simple dielectric model, which models the interior as a low dielectric sphere, combined with Monte Carlo simulations, shows that for small, hydrophilic proteins the effect of the low dielectric interior is largely negligible and that the protein (and solution) can be approximated with a uniform high dielectric constant equal to that of the solvent. This is verified by estimates of titration curves and acidity constants for four different proteins (BPTI, calbindin D(9k), ribonuclease A, and turkey ovomucoid third domain) that all correlate well with experimental data. Furthermore, the high dielectric approximation follows as a natural consequence of the multipole expansion of the potential due to embedded protein charges in the presence of the low dielectric core region.
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PMID:Implications of a high dielectric constant in proteins. 1758 Oct 83

Electrostatic interactions in proteins can be probed experimentally through determination of residue-specific acidity constants. We describe here triple-resonance NMR techniques for direct determination of lysine and arginine side-chain protonation states in proteins. The experiments are based on detection of nonexchangeable protons over the full range of pH and temperature and therefore are well suited for pKa determination of individual amino acid side chains. The experiments follow the side-chain 15Nzeta (lysine) and 15Nepsilon or 13Czeta (arginine) chemical shift, which changes due to sizable changes in the heteronuclear electron distribution upon (de)protonation. Since heteronuclear chemical shifts are overwhelmed by the charge state of the amino acid side chain itself, these methods supersede 1H-based NMR in terms of accuracy, sensitivity, and selectivity. Moreover, the 15Nzeta and 15Nepsilon nuclei may be used to probe changes in the local electrostatic environment. Applications to three proteins are described: apo calmodulin, calbindin D9k, and FKBP12. For apo calmodulin, residue-specific pKa values of lysine side chains were determined to fall between 10.7 and 11.2 as a result of the high net negative charge on the protein surface. Ideal two-state titration behavior observed for all lysines indicates the absence of significant direct charge interactions between the basic residues. These results are compared with earlier studies based on chemical modification.
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PMID:Residue-specific pKa determination of lysine and arginine side chains by indirect 15N and 13C NMR spectroscopy: application to apo calmodulin. 1804 88

Parkinson's disease (PD) is a chronic neurodegenerative disease with no cure. Calbindin, a Ca²⁺-buffering protein, has been suggested to have a neuroprotective effect in the brain tissues of PD patients and in experimental models of PD. However, the underlying mechanisms remain elusive. Here, we report that in 1-methyl-4-phenylpyridinium (MPP⁺)-induced culture models of PD, the buffering of cytosolic Ca²⁺ by calbindin-D28 overexpression or treatment with a chemical Ca²⁺ chelator reversed impaired autophagic flux, protecting cells against MPP⁺-mediated neurotoxicity. When cytosolic Ca²⁺ overload caused by MPP⁺ was ameliorated, the MPP⁺-induced accumulation of autophagosomes decreased and the autophagic flux significantly increased. In addition, the accumulation of damaged mitochondria and p62-positive ubiquitinated protein aggregates, following MPP⁺ intoxication, was alleviated by cytosolic Ca²⁺ buffering. We showed that MPP⁺ treatment suppressed autophagic degradation via raising the lysosomal pH and therefore reducing cytosolic Ca²⁺ elevation restored the lysosomal pH acidity and normal autophagic flux. These results support the notion that functional lysosomes are required for Ca²⁺-mediated cell protection against MPP⁺-mediated neurotoxicity. Thus, our data suggest a novel process in which the modulation of Ca²⁺ confers neuroprotection via the autophagy-lysosome pathway. This may have implications for the pathogenesis and future therapeutic targets of PD.
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PMID:Buffering of cytosolic calcium plays a neuroprotective role by preserving the autophagy-lysosome pathway during MPP⁺-induced neuronal death. 3145 56

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