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Related Concept Videos

Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Amino acids03:42

Amino acids

Amino acids are the monomers that comprise proteins. Each amino acid has the same fundamental structure, which consists of a central carbon atom, or the alpha (α) carbon, bonded to an amino group (NH2), a carboxyl group (COOH), and to a hydrogen atom. Every amino acid also has another atom or group of atoms bonded to the central atom known as the R group. There are 20 common amino acids present in proteins, each with a different R group. Variation in the amino acid sequence is responsible for...
Basicity of Heterocyclic Aromatic Amines01:25

Basicity of Heterocyclic Aromatic Amines

Heterocyclic amines, where the N atom is a part of an alicyclic system, are similar in basicity to alkylamines. Interestingly, the heterocyclic amine having a nitrogen atom as part of an aromatic ring has much less basicity than its corresponding alicyclic counterpart. For this reason, as presented in Figure 1, piperidine (pKb = 2.8) is significantly more basic than pyridine (pKb = 8.8).
Porin Insertion in the Outer Mitochondrial Membrane01:12

Porin Insertion in the Outer Mitochondrial Membrane

Porins are beta-barrel proteins translocated to the mitochondrial outer membrane through the TOM complex into the intermembrane space. Porin precursors bind TIM chaperones within the intermembrane space and are guided to the Sorting and Assembly Machinery complex or SAM complex on the outer mitochondrial membrane.
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Basicity of Aromatic Amines01:18

Basicity of Aromatic Amines

The basicity of aromatic amines is much weaker than that of aliphatic amines due to the involvement of the lone pair of electrons over the N atom in resonance with the aryl rings. Generally, the electron-donating ability of any substituents on the aryl ring of aromatic amines increases the basicity of the amine by increasing electron density, and hence the availability of lone pair on the nitrogen. On the other hand, electron-withdrawing functional groups on the aryl ring of amines decrease the...
Basicity of Aliphatic Amines01:21

Basicity of Aliphatic Amines

Amines can behave as Brønsted–Lowry bases by accepting a proton from the acid to form corresponding conjugate acids. Due to a lone pair of nonbonding electrons, aliphatic amines can also act as Lewis bases by forming a covalent bond with an electrophile.
To measure the basicity of amines, two conventions are generally used. The first defines Kb as the basicity constant for the deprotonation reaction of water by the amine, as presented in Figure 1. Conventionally, lower Kb indicates higher...

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Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions
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Aspartate embedding depth affects pHLIP's insertion pKa.

Justin Fendos1, Francisco N Barrera, Donald M Engelman

  • 1Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, Connecticut 06520, United States.

Biochemistry
|June 1, 2013
PubMed
Summary
This summary is machine-generated.

Altering aspartate depth in pH-low insertion peptides (pHLIP) modifies their pH-dependent membrane insertion. This finding offers new ways to improve pHLIP performance for targeting acidic diseases like cancer.

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Area of Science:

  • Biophysics
  • Membrane protein insertion
  • Peptide-lipid interactions

Background:

  • pH-low insertion peptides (pHLIP) insert into lipid bilayers at low pH.
  • Insertion involves protonation of aspartate residues in the peptide's transmembrane domain.
  • The depth of aspartate residues influences insertion hydrophobicity and pH-dependence.

Purpose of the Study:

  • To investigate the role of aspartate residue depth in pH-dependent transmembrane peptide insertion.
  • To determine how altering aspartate depth affects the proton affinity and insertion pKa of pHLIP.
  • To explore if arginine mutations modulate insertion pKa by affecting aspartate depth.

Main Methods:

  • Created pHLIP sequence variants with modified aspartate positions (D14, D25).
  • Mutated arginine at position 11 to assess its effect on aspartate depth and pKa.
  • Measured changes in insertion pKa and aggregation resistance of pHLIP variants.

Main Results:

  • Mutations altering aspartate depth significantly changed the insertion pKa.
  • Arginine mutation at position 11 also modulated insertion pKa, suggesting an effect on aspartate depth.
  • pHLIP aggregation resistance was altered by mutations, indicating a new performance criterion.

Conclusions:

  • Aspartate depth is a key parameter in determining the pH dependence of pHLIP insertion.
  • Modifying aspartate depth and considering arginine interactions can tune pHLIP insertion characteristics.
  • These findings provide a basis for enhancing pHLIP performance in vivo for disease targeting.